CN107567334A - Dehelminthization combines and its application method - Google Patents

Abstract

The present invention relates to veterinary composition, at least one cyclic depsipeptide and at least one macrolide comprising effective dose；And pharmaceutically acceptable carrier, it is used to treat or prevent the parsitism in mammal, wherein the parasitic animal and plant shows the resistance to individually being handled or being prevented with macrolide.

Description

Dehelminthization combines and its application method

Addition is quoted in relevant application

The priority benefit for the U.S. Provisional Application No. 62/142304 submitted this application claims on April 2nd, 2015, passes through Quote and be fully incorporated herein.

Any aforementioned application and the whole documents (" application literature cited ") wherein or during its application process quoted and Apply for whole documents that literature cited is quoted or reference, and herein cited or reference whole documents (" this paper institutes quotation Offer "), and all documents cited herein quote or reference whole documents, and herein or any text for being incorporated herein by quoting Guide, specification, product description and the description of product page of any manufacturer of any products referred in offering, herein by Quote and be incorporated herein and can be used in the practice of the present invention.Any document is quoted or specified in the application it is not an admission that this article It is prior art of the invention to offer.

Invention field

The present invention relates to dehelminthization combination, and it includes at least one macrolide and at least one cyclic depsipeptide, for controlling Treat parasitics resistance worm or helminth infection.The present invention also relates to the purposes that medicine is prepared with compound；And it is related to treatment, It includes the mammal that compound is given needs and treated.In addition, the present invention relates to the pharmaceutical composition of inclusion compound and Kit.The present invention also provides the ameliorative way of elimination, control and prevention mammal parasitic infestations.

Background of invention

Animal such as mammal and birds are usually easily attacked by parasitic animal and plant.These parasitic animals and plants can be ectoparasite such as Insect, and endoparasite such as filaria and worm.Animals and humans, which also suffer from endoparasite infection, includes such as verminosis, and it is most The parasite for being continually described as nematode or worm by one kind causes.These parasitic animals and plants cause pig, sheep, tight in horse, and ox Weigh economic loss and influence livestock and poultry.Other parasitic animals and plants present in animals and humans intestines and stomach include Ancylostoma (Ancylostoma), Necator (Necator), Ascaris (Ascaris), Strongyloides (Strongyloides), Trichinella (Trichinella), Hepaticola (Capillaria), Belascaris (Toxocara), Toxascaris (Toxascaris) parasitic animal and plant existing for, Trichocephalus, Enterobius (Enterobius) and blood or other tissues and organ is such as The parenteral stage of filaria and Strongyloides, Belascaris (Toxocara) and Trichinella (Trichinella).

A kind of endoparasite for seriously endangering mammal is heart worm (Dirofilariaimmitis), is also referred to as disliked Filaria.Most common host is dog and cat, but other mammals such as ferret and racoon can also be infected.Heart worm By several life stages, then they are changed into adult, the pulmonary artery of infection host mammal.Worm is needed in mosquito conduct Between the stage complete its Life Cycles.The primary infection that mosquito is bitten in dog lives in it in heart with worm maturation for adult Between period 6 to 7 months are needed in dog, and be referred to as " appearing the preceding period (prepatent period) ".L3 larvas Migrated during mosquito ingests blood to mosquito mouthparts (lower lip), leave mosquito and calmness on dog skin, then they Herein host is migrated into by biting wound.Husking is most L3 larvas in dog hypodermis in 1-3 days after infection Four instar larvaes (L4s).Then, they are migrated to chest and abdomen muscle, and after infection 45 to 60 days husking for five ages (L5, Immature adult).75 to 120 days after infection, these immature heart worms pass through subsequently into blood flow and carrying Heart, reside in pulmonary artery.About 7 months after infection, heart worm (Dirofilaria immitis) adult reaches Maturity period and the generative propagation in pulmonary artery and right ventricle.Male insect is about 15cm and female is then about 25cm, and it As adult ordinary life according to being calculated as about 5 years.After mating, female worm is referred to as microfilaria (or L1) larva It is released into circulation.Microfilaria was circulated in blood flow up to 2 years, waited in its Life Cycles in the next of mosquito enteral that suck blood Stage.In the case where being swallowed by mosquito, a series of huskings, which occur, for microfilaria turns into communicable three instar larvae, then migrates To the glandula of mosquito, they wait the another host of infection herein.

Infection by Dirofilaria immitis is serious and life-threatening disease.Infection by Dirofilaria immitis is preventible and dislikes silk in dog Prevention processing is preferential in worm Prevalent district.Adult heart worm is handled with adulticide (such as Melarsomine dihydrochloride) Infection is high cost and can result in serious adverse side effect, is interrupted so as to be widely used that by monthly giving medicine Larva is developed to be prevented.The preventative-therapeutic purpose of heart worm in dog is by following stopping heart worm senses Dye：Go out and remove by mosquito calmness and initially enter four ages in the stage in dog, three instar larvaes (L3), and childhood and maturation Phase larva (L4).The dog that macrolide (MLs) monthly can be used to be uninfected by is to suppress adult breeding and remove microfilaria, thus Reduce and propagate and gradually cause adult to reduce (Veterinary Parasitology 2005Oct 24 133 (2-3) 197- 206)。

Macrolide (such as Ivermectin HCL, it is close than mycin oxime, Moxidectin (moxidectin), and selamectin (selamectin)) it is most generally used chemopreventive agent and is given with the moon or six months for interval.These medicines have The instar larvae of heart worm three (L3) and L4 that the confrontation of effect ground developed in first 30 days, so as to prevent the disease as caused by adult.

However, reporting increased number of effect in recent years lacks (LOE) situation, wherein although monthly receiving preventative dose The macrolides of amount, dog still develop adult infection by Dirofilaria immitis.For example, Atkins et al. (Veterinary Parasitology 206 (2014) 106-113) report that increased number of dog measures the situation of heart worm antigen positive recently, Although receive heart worm preventive administration；This means the selectivity to heart worm prophylactic has been developed in heart worm Resistance (American Heartworm Society, 2010.Heartworm Preventive Resistance.Is it Possible,vol.37.Bulletin of the American Heartworm Society,pp.5.).Reported recently Research in, identified in the infection by Dirofilaria immitis model of induction, especially JYD-34 heart worms strain dog dislike silk Worm separation strains show the preventative product neurological susceptibility of heart worm (Blagburn the et al., Comparative less than 100% efficacy of four commercially available heartworm preventive products against the JYD-34 laboratory strain of Dirofilaria immitis.In:Proceedings of the P.39, Triennial Heartworm Symposium, vol.14, (make a summary)；With Blagburn et al., Evidence of genetic selection following treatment of a heartworm-infected,microfilaremic Dog with increasing dosages ofivermectin [summary] .Proc.Am.Assoc.Vet.Parasitol.58,31.)。

Many researchs have shown that heart worm larva is anti-to certain of macrolide such as Ivermectin HCL and Mi Bi mycin oximes Property.(J.Vet.Intern.Med.2011；25:61-64 and Can.Vet.J.2011Dec；52(12):1279-1280).Recently It has been reported that, high-frequency genotypic markers thing is related to potential big ring resistance, such as some heart worm strains are encoding The site 11 and 618 (GG-GG) of the gene of P- glycoprotein has mononucleotide polymorphic phenomenon, show to Ivermectin HCL certain is anti- Property (Topics in Companion Animal Medicine Volume 26, Issue 4, November 2011, Pages 186-192；Veterinary Parasitology 176(2011)374-381；With Parasites＆Vectors 2014,7: 494).In addition, nearest report is pointed out to use Ivermectin HCL, it is close to handle heart worm MP3 strains than mycin oxime or selamectin Incomplete effect (the http of common prevention scheme://www.delawarevalleyacademyvm.org/pdfs/may11/ 1Canine_Heart worm_2011.pdf；With Veterinary Parasitology 176 (2011) 189-194) ".These Report shows that the effect of most macrolides can no longer be to whole heart worm strains all 100%.

US 2011/0263489, US 8709440, US 2014/0163056, US 2012/0295931, AU 2010249226 and AU2010101389 describes the dehelminthization composition of micellar solution, comprising at least two anthelmintics, Wherein anthelmintic is used to handle the parasitic animal and plant to one or more anti-parasitic compound resistances.

US 6,159,932 describes Avermectins (avermectins), Ivermectin HCL and Mi Bi mycin classes (milbemycins) mixture and cyclic depsipeptide in combination, optionally in the presence of praziquantel or epsiprantel, for Kill increase in endoparasite composition and kill endoparasite effect.

US 2011/0046072 describes to delay the solid pharmaceutical preparation of release, comprising at least one pharmacy activity component, its Depsipeptides and/or macrolide and PVP or derivatives thereof can be included.

Although described in above-mentioned document comprising independent Ai Modesi or macrolide or its combine with other activating agents Composition, it is still necessary to which veterinary composition and method, there is improved effect and covering spectrum to protect mammal confrontation to post for it Resistance of the biology for the continuous evolution of current various processing.

Brief summary of the invention

The present invention relates to the combination of at least one cyclic depsipeptide of effective dose and at least one macrolide, for treating or Prevent the parasitic animal and plant of mammal especially cat, dog and people, the purpose is to all parasitisms typically met with are removed from these hosts Thing, parasitic animal and plant especially resistant at least one anthelmintic macrolide.

In some embodiments, the present invention also be provided with effect and it is lasting for a long time to mammalian digestive tract endoparasitism Thing, the destruction of nematode, such as filaria, hookworm, whipworm and roundworm.

In embodiments, the present invention provides the composition and method of prevention heart worm disease, and the disease is by right Caused by the resistant heart worm strain of macrolide.In special embodiment, the present invention provides prevention heart worm The composition and method of disease, the disease are as caused by heart worm (Dirofilaria immitis) resistant strain.

Especially, the present invention provides the combination of at least one macrolide derivatives and at least one cyclic depsipeptide, its with Only adduction activity or synergistic activity of the preparaton containing macrolide compared to displaying to parasitic animal and plant.The present invention also provides for lactation and moved The convenient method of parasitic animal and plant invasion and attack or prevention parasitic animal and plant invasion and attack is handled in thing, it can include combining the present invention of effective dose Thing gives the mammal.

These and other embodiment is able to disclosure by following detailed descriptions or is become obvious and covered by it.

Detailed description of the invention

Term used herein is by with their conventional sense in this area, unless otherwise specified.

It should be noted that the present invention be not intended to cover in the present invention any previously known product, the process for preparing product or Using the method for product, so as to applicant's rights reserved and it is disclosed to any previously known product, process or method Exclude.It should also be noted that the present invention is not intended in the preparation or use of covering any product, process or product in the scope of the invention The method of product, it does not meet USPTO (the 1st section of (35U.S.C.) 112) or EPO (the 83rd article of EPC) written description and implementation It is required that；So as to applicant's rights reserved and be disclosed removing property term such as " substantially by ... form " with " substantially by ... There is composition " U.S. Patent Laws to assign their implication, such as they allow the key element that does not explicitly point out, but exclude existing Key element present in technology influences essential characteristic of the present invention or the key element of new feature.

It should also be noted that in the disclosure and particularly in claim and/or paragraph, term such as " including ", " bag The implication from U.S. Patent Laws can be had by including ", " contain " etc.；Such as they can mean " covering ", " forgiving ", " cover Cover " etc..

Unless otherwise specifically indicated or by context, it is apparent that " activating agent " or " active component " or " therapeutic agent " such as It is used in this specification, it is intended that dehelminthization compound of the invention and/or cyclic depsipeptide.

In addition, " one " or " one kind " is used for describing to the key element and component of the present invention.This is merely for convenience and is this Invention provides universal.The description is understood to include one or at least one, and odd number also includes plural number, unless otherwise It is explicitly indicated.

Term " order " or " successively " be as used herein to be referred in a manner of (two kinds of directions) order, for example, with one or Multiple minutes, hour, day or the spaced apart of week give each activating agent；And if appropriate, activating agent can be regularly to weigh Multiple circulation is given.If there is sequentially giving, delay to give effective effect benefit that one of activating agent should not lose activating agent combination Place.In the whole circumstances that " order " is given, method of administration can be identical or different.

Term " associated " or " simultaneously " refer at least two activating agents as used herein while give mammal." " in the whole circumstances given, method of administration can be identical or different together.

Term " mammal " includes but is not limited to cat, dog and the mankind as used herein.It is additionally included in all development ranks The independent mammal of section, including embryo and the fetal state.

Term " effective dose " is as used herein it is meant that after composition is given to animal, and activating agent is in the composition Concentration is enough to cause the hope biological answer-reply to target parasitic animal and plant, and its measuring method is known in the art and/or is described in In embodiment hereof.In some embodiments, " effective dose " of activating agent in the composition will provide and untreated control phase Than at least 80% or at least 85% effect.More generally, " effective dose " of activating agent will be provided to target parasitic animal and plant at least 90%, at least 93%, at least 95% or at least 97% effect.In some embodiments, including by heart worm resistance product In the prevention of heart worm disease caused by system, term " effective dose " can provide up to 100% effect.

Term " treatment ", " processing " etc. it is as used herein (unless otherwise specified) refer to eliminate or improve parsitism, Infect or the patient's condition.It also includes reducing infection time section or parsitism symptom incidence, and is related to " preventing and treating " and (such as goes out Remove, repellent, discharge, make impotentia, elimination, mitigation, minimum and elimination).

Term " with single macrolide therapy or prevention " refer to as used herein with macrolide therapy or prevention and Treated or prevented without cyclic depsipeptide.

Term " prevention " or " preventative " or " prevention sex therapy ", " prevention " or " strick precaution " include causing as referred to herein Parsitism is infected and does not occur or hinder, takes precautions against or prevent as caused by parsitism disease to occur；Such as this paper institutes With depending on the condition of mammal, these terms are also covered by preventing obstacle or the patient's condition before infecting or infecting described in sufferer Breaking-out or the paresthesia epilepsy relevant with obstacle or the patient's condition.For example, give the present composition to mammal so as to prevent by Heart worm disease caused by heart worm resistant strain：Gone out in mammal except three instar larvaes (L3), and childhood and Four instar larvaes (L4) in maturation so that it is adult that they are immature.So as to which these terms can refer to the compounds of this invention Give and not suffer from infection or the mammal infected in administration time.As used herein, these terms are also covered by prevention infection Or infect recurrence or the recurrence of associated symptom.

Term " resistance ", " anti-" etc. refer to that parasitic animal and plant shows and treatment or prevention are prolonged (unless otherwise specified) as used herein Slow, reduction and/or unresponsive ability, described treat or prevent use the single macrolide for treating recommended dose (i.e. not Handled with cyclic depsipeptide), the parasitic animal and plant of identical type and age generally can be treated or take precautions against to the dosage.For example, (handled after being handled with single macrolide without cyclic depsipeptide), the mammal with infecting non-resistance parasitic animal and plant strain The amount that the parasitic animal and plant carrying capacity shown reduces is compared, infection macrolide-resistant parasites (such as resistance heart worm strain) The parasitic animal and plant carrying capacity of mammal can reduce less degree.The term is used for including the resistant form ratio that can separate identification Such as " complete resistance ", " immune ", " partial resistance ", " supersensitivity " and " tolerance ".Term also includes the lactation of parsitism Animal, it is unresponsive (" nonresponder ") to handling parsitism with macrolide；And the mammal of parsitism, It suffers from recurrence (" respondent-recidivist ") after handling parsitism with macrolide.

Term " pharmaceutically acceptable " means that being applied to contact in the good determination range of veterinary science feeds as used herein Newborn zooblast and match without excessive toxicity, stimulation, allergic reaction etc., and with rational interests/Hazard ratio.

In specific embodiment, term " about " or " about " mean the 20% of set-point or scope, preferably 10% He Within more preferably 5%.

In the case where the compounds of this invention alkalescence or acidity enough are to form stabilization non-toxic acid or alkali salt, compound can In the form of in pharmaceutically acceptable salt.Pharmaceutically acceptable salt include derived from pharmaceutically acceptable inorganic base and acid or Those of person's organic base and acid.Suitable salt includes being derived from those following：Alkali metal such as potassium and sodium, alkaline-earth metal is such as Calcium and magnesium, and its many other acid well known in the art.Especially, the example of pharmaceutically acceptable salt is that have with what acid was formed Machine acid-addition salts, the acceptable anion of its physiology, such as toluene fulfonate, mesylate, acetate, citric acid Salt, malonate, tartrate, succinate, benzoate, ascorbate, alpha-ketoglutarate, and α-phosphoglycerol Salt.Suitable inorganic salts, including sulfate, nitrate, bicarbonate and carbonate can also be formed.

Pharmaceutically acceptable salt can be obtained with standardization program well known in the art, such as by compound alkaline enough For example amine is physiologically subjected to the suitable acid reaction of anion with providing.Alkali metal (such as sodium, the potassium of carboxylic acid can also be prepared Or lithium) salt or alkaline-earth metal (such as calcium) salt.

In one embodiment, the present composition includes effective dose：

A) at least one cyclic depsipeptide；

B) at least one macrolide；With

C) pharmaceutically acceptable carrier；

It is used to treat or prevent the parsitism in mammal, and wherein parasitic animal and plant is shown at least one big ring The resistance of ester.

In yet another embodiment, the present composition also includes praziquantel.

In another embodiment of the invention, parasitic animal and plant is heart worm (Dirofilaria immitis), particularly It is resistance heart worm strain, it contains the mononucleotide polymorphic phenomenon of coding P- glycoprotein transport albumen, and it is in coding P- sugar The site 11 and 618 (GG-GG) of the gene (" GG-GG " genotype) of albumen includes homozygous G residue.In the present invention again In one embodiment, parasitic animal and plant is the heart worm strains of JYD 34, MP3 heart worms strain or its combination.

In another embodiment of the invention, parasitic animal and plant is heart worm (Dirofilaria immitis) three ages Phase larva (L3) or four instar larvaes (L4) or its combination.

In another embodiment of the invention, cyclic depsipeptide is 24- member cyclooctadepsipeptides.

In another embodiment of the invention, cyclic depsipeptide is Ai Modesi, PF1022A, PF1022A derivatives, or It is combined；More particularly Ai Modesi.

In another embodiment of the invention, the macrolide of composition is AVM (avermectin), close ratio Mycin (milbemycin) or its combination；More particularly, macrolide is selected from AVM, Dimasdectin, doramectin, first Rhzomorph (latidectin), thunder cuticulin (lepimectin), department are replaced in amino AVM, Eprinomectin, Ivermectin HCL, drawing Clarke fourth (selamectin), it is close than mycin oxime and Moxidectin (moxidectin) or its combination；More particularly, according to dimension bacterium Element, Eprinomectin or Moxidectin.

In another embodiment of the invention, the effective dose of macrolide and cyclic depsipeptide is enhancing effective amount.

In another embodiment of the invention, the weight ratio of macrolide and cyclic depsipeptide is about 1:500 to about 1: 1000, about 1:833,1:750 to about 1:1000,1:500 to about 1:750, about 1:250 to about 1:500, about 1:417, about 1:100 To about 1:250, about 1:167,1:150 to about 1:200, or about 1:50 to about 1:100.It is highly preferred that macrolide contracts with ring-type The weight ratio of peptide is about 1:100 to about 1:1000, or about 1:500 to about 1:1000.

In another embodiment of the invention, the weight ratio of macrolide and praziquantel is about 1:50 to 1:5000, more Preferably from about 1:500 to about 1:5000, or about 1:3500 to about 1:5000.

In another embodiment of the invention, veterinary composition is oral preparaton, injectable preparaton, is locally matched somebody with somebody Preparation, sprinkle and pour agent preparaton, skin preparaton or subcutaneous preparaton；It is preferred that oral preparaton, soft chewable composition or chewing Tablet composition.

In another embodiment of the invention, the parasitic animal and plant of the present composition and method preventing and treating is shown to selected from following At least one macrolide resistance：AVM, Dimasdectin, doramectin, emamectin benzoate, Yi Linuoke Rhzomorph replace in fourth, Ivermectin HCL, drawing, thunder cuticulin, selamectin, close than mycin-oxime, and Moxidectin or its combine；Particularly It is Ivermectin HCL.

In another embodiment of the invention, mammal is selected from people, dog and cat；More particularly dog or cat.

Another embodiment of the invention is veterinary composition, includes enhancing effective amount：

A) Ai Modesi；With

B) Ivermectin HCL；With

Pharmaceutically acceptable carrier；

It is used to treat or prevent parsitism, and wherein parasitic animal and plant is resistance heart worm strain, and parasitic animal and plant is particularly Ground is three instar larvaes (L3) or four instar larvaes (L4) or its combination of resistance heart worm strain.

In another embodiment of the invention, veterinary composition also includes praziquantel.

Another aspect of the present invention is the method that parsitism is treated or prevented in mammal, including to the food in one's mouth Newborn animal gives effective dose：

A) at least one cyclic depsipeptide；With

B) at least one macrolide；

And pharmaceutically acceptable carrier；

Wherein parsitism includes the parasitic animal and plant resistant at least one macrolide.

Another embodiment of the invention be treat or prevent parsitism method, wherein parsitism include pair Macrolide therapy is used alone or prevents resistant parasitic animal and plant.

Another embodiment of the invention is the method that parsitism is treated or prevented in mammal, also comprising pyrrole Quinoline ketone or epsiprantel or its combination.

Another embodiment of the invention is the method that parsitism is treated or prevented in mammal, wherein effectively Amount is enhancing effective amount.

Another embodiment of the invention is the method that parsitism is treated or prevented in mammal, wherein parasitic Thing is heart worm (Dirofilaria immitis).

Another embodiment of the invention is the method that parsitism is treated or prevented in mammal, wherein parasitic Thing is resistance heart worm strain.

Another embodiment of the invention is the method that parsitism is treated or prevented in mammal, wherein parasitic Thing is three instar larvaes (L3) or four instar larvaes (L4) or its combination of resistance heart worm strain

Another embodiment of the invention is the method that parsitism is treated or prevented in mammal, wherein ring-type Depsipeptides is 24- member cyclooctadepsipeptides；More particularly Ai Modesi, PF1022A, PF1022A derivative or its combination.PF1022A spreads out The example of biology includes being described in Ohyama, M., et al., Biosci.Biotechnol.Biochem., 75 (7), 1354- Those cyclic depsipeptide compounds of 1363,2011 tables 2, are fully incorporated herein.More particularly, PF1022A derivatives include Cyclic depsipeptide compound, is selected from：

Another embodiment of the invention is the method that parsitism is treated or prevented in mammal, wherein ring-type Depsipeptides is Ai Modesi.

Another embodiment of the invention is the method that parsitism is treated or prevented in mammal, wherein giving Macrolide be AVM (avermectin), it is close than mycin (milbemycin) or its combination.

Another embodiment of the invention is the method that parsitism is treated or prevented in mammal, wherein giving Macrolide be selected from AVM, Dimasdectin, doramectin, emamectin benzoate, Eprinomectin, according to dimension bacterium Rhzomorph replace in element, drawing, thunder cuticulin, selamectin, it is close than mycin oxime and Moxidectin or its combine.

In another embodiment of the invention, there is provided the method that parsitism is treated or prevented in mammal, Combination including giving from effective dose to mammal, it includes and is selected from following macrolides：AVM, Dimasdectin, Rhzomorph is replaced in doramectin, emamectin benzoate, Eprinomectin, Ivermectin HCL, drawing, thunder cuticulin, and selamectin is close than mould Plain oxime and Moxidectin or its combination；With selected from following cyclic depsipeptides：Ai Modesi, PF1022A, PF1022A derivative or It is combined.

Another embodiment of the invention is the method that parsitism is treated or prevented in mammal, wherein combining The macrolide of thing is Ivermectin HCL.

Another embodiment of the invention is the method that parsitism is treated or prevented in mammal, and it includes head Mammal first is handled with adulticide such as Thiacetarsamide Sodium or Melarsomine dihydrochloride, with following processing after 3 to 6 weeks： A) at least one cyclic depsipeptide；And b) at least one macrolide；And pharmaceutically acceptable carrier；Wherein parsitism bag Containing the parasitic animal and plant resistant at least one macrolide.Another embodiment of the invention is the treatment or pre- in mammal The method of anti-parsitism, it also includes being handled with A Fu Ranas.

Another embodiment of the invention be in mammal treat or prevent parsitism method, its Chinese veterinarian It is oral preparaton to learn composition, injectable preparaton, topical formulations, sprinkles and pours agent preparaton, skin preparaton or is subcutaneously matched somebody with somebody Preparation, or more preferably there is the oral preparaton of soft chewable composition or chewable tablet composition.

Another embodiment of the invention is the method that parsitism is treated or prevented in mammal, wherein parasitic Thing is shown to the resistance selected from following at least one macrolides：AVM, Dimasdectin, doramectin, methylamino Rhzomorph is replaced in AVM, Eprinomectin, Ivermectin HCL, drawing, and thunder cuticulin, selamectin is close than mycin-oxime, and not former times gram Fourth or its combination；More particularly Ivermectin HCL.

Another embodiment of the invention be in mammal treat or prevent parsitism method, wherein lactation Animal is selected from people, dog and cat, more particularly dog or cat.

Another embodiment of the invention is the method that parsitism is treated or prevented in mammal, including to the food in one's mouth Newborn animal gives enhancing effective amount：

A) Ai Modesi；With

B) Ivermectin HCL；

And pharmaceutically acceptable carrier；

Wherein parasitic animal and plant is resistance heart worm strain.

Another embodiment of the invention is the method that parsitism is treated or prevented in mammal, and it is also included Praziquantel.

Another embodiment of the invention is the method that parsitism is treated or prevented in mammal, wherein parasitic Thing infection causes the mammal respiratory disease relevant with heart worm.

Another embodiment of the invention is the method that parsitism is treated or prevented in mammal, wherein ring-type The administration of depsipeptides and macrolide is associated.

Another embodiment of the invention is the method that parsitism is treated or prevented in mammal, wherein ring-type The administration of depsipeptides and macrolide is successively.

Another embodiment of the invention is the method that parsitism is treated or prevented in mammal, and it also includes Presence of the resistant parasites strain in mammal is detected, then gives the composition to mammal.

Another embodiment of the invention is the method that parsitism is treated or prevented in mammal, wherein resistance Parasitic animal and plant strain is resistance heart worm strain.

Another embodiment of the invention is the method that parsitism is treated or prevented in mammal, wherein being administered Selected from intestines, oral, parenteral, part or cutaneous penetration.

Another embodiment of the invention is kit, wherein the kit includes：

I) at least one container；

Ii) at least one cyclic depsipeptide of enhancing effective amount and at least one macrolide；With pharmaceutically acceptable load Body；With

Iii) by the parsitism of cyclic depsipeptide and macrolide for treating or preventing resistance heart worm strain Guiding book.

Another embodiment of the invention is kit, and it also includes praziquantel.

Another embodiment of the invention is kit, wherein cyclic depsipeptide and macrolide in same containers or separated In container.

Another embodiment of the invention is kit, and wherein container is selected from blister package, bottle, pouch, ampoule, injection Device, pill rifle (pill popper) device, Filling gun, spray gun, sprinkle and pour device, pipette, dropper, application device, Huo Zheshi In any other container for accommodating agricultural chemicals, or its combination.

Another embodiment of the invention is kit, and it, which is also included, is used to give cyclic depsipeptide and big ring to mammal Doser.

Another embodiment of the invention is kit, and wherein doser is selected from syringe, pill gun apparatus, perfusion Bottle, Filling gun, spray gun, transdermal patch, sprinkle and pour device, pipette dropper, liniment device, ear label, necklace, or suitable for by medicine Thing gives any other device of mammal, or its combination.

Another embodiment of the invention is kit, and it, which is also included, is used to detect heart worm such as heart worm strain The diagnostic tool that whether there is.

Another embodiment of the invention is kit, and wherein diagnostic tool is detection test, and it detects heart worm example Combination of the nucleic acid primer to, nucleic acid primer pair such as heart worm strain whether there is, and nucleic acid test (such as diagnostic card) contains The combination of nucleic acid primer pair or nucleic acid primer pair.

Another embodiment of the invention is the method for preventing parsitism in mammal, including by of the present invention group Compound gives the mammal, and it is parasitic to include at least one resistant at least one macrolide for wherein parsitism Thing.

Another embodiment of the invention is the method for preventing parsitism in mammal：By the present composition Give mammal and remove three instar larvaes (L3) of heart worm and four instar larvaes (L4) in childhood and maturation to go out, So that it is adult that they are immature.

Another embodiment of the invention is the dosage described by treatment group 4 or 5, preparaton, method of administration in embodiment Or dosage regimen.Purposes and method are also provided, are used for prevention or treatment birds or mammal comprising the present composition In parasitic infestations or for preparing medicine, the parasitic animal and plant that the medicine is used in prevention or treatment birds or mammal is invaded Dye.

Endoparasite infection that macrolide anthelmintic compound can be used for handling in mammal and birds and outer Parsitism.The compound for belonging to category macrolide includes but is not limited to AVM (avermectin) and close than mould The compound of plain (milbemycin) series.These compounds are to the effective anti-parasitic of the inside and outside parasitic animal and plant of wide scope Agent.Avermectins and Mi Bi mycins class all have identical 16- membered macrolide rings；However, it is close than mycin class without interior Disaccharides substituent on ester ring 13- positions.In addition to handling parasitic animal and plant insect, Avermectins and Mi Bi mycins class are also used for locating Manage the endoparasite such as nematode infections in mammal.

Avermectins can be isolated from deinsectization streptomycete (Streptomyces avermitilis) and its derivative Produce the fermentation broth of AVM bacterial strain.Production, separation and the structure determination of Avermectins are recorded in Albers- Schonberg, et al, J.Am.Chem.Soc.1981,103,4216-4221 and draw in bibliography.Culture morphology The description of feature is referring to the U.S. patent No.s 4,310,519.It is naturally close to be described in Aoki et than mycin class (milbemycins) Al. U.S. patents 3,950,360, it is fully incorporated herein by quoting, and be described in " The Merck Index " 12^thEd., draw in S.Budavari, Ed., Merck＆Co., Inc.Whitehouse Station, New Jersey (1996) Various bibliography.

The compound of AVM and Mi Bi mycins series is natural prodcuts or semi-synthetic derivative.Natural prodcuts AVM hereinafter Bacteriums are disclosed in the U.S. patent No.s 4, and 310,519, and 22,23- dihydro avermectin compounds are disclosed in the U.S. patent No.s 4, 199,569, both of which is incorporated herein by quoting.Synthesis Avermectins have been described (J.Am.Chem.Soc.1989, 111,2967；J.Am.Chem.Soc.1986,108,2776), and avermectin derivatives dissociation and epimerization are ground Study carefully and be also described in Hanessian, et al (J.Am.Chem.Soc.1987,109,7063) and Fraser-Reid, et al (J.Am.Chem.Soc.1987,109,933).The general discussion of Avermectins, including they the use in human and animal Way discusses, referring to " Ivermectin and Abamectin, " W.C.Campbell, ed., Springer-Verlag, New York(1989).The example of Avermectins includes but is not limited to AVM, Dimasdectin, doramectin, methylamino Ah Rhzomorph is tieed up, Eprinomectin, Ivermectin HCL, draws and replaces rhzomorph, thunder cuticulin and selamectin.

Close is the glycosyl derivatives of matching somebody with somebody of Avermectins than mycin class, such as the U.S. patent No.s 4,144,352,4,791, 134 and 6, those described in 653,342 are fully incorporated herein by quoting.The especially important anthelmintic of the family Including Moxidectin, such as U.S. patent No.s 7,348,417 and 4,916,154 (and references cited therein) are described in, It is fully incorporated herein by quoting.The close example than mycin class also includes milbemectin, close than mycin D and nemadectin. Respectively, it is also included be Avermectins and Mi Bi the mycin class 5- oxos and 5- 9 oxime derivates.

Macrocyclic lactone compounds are known in the art and can be easily commercially available or by known in the art Synthetic technology obtains.Reference can be made to the technology and trade literature that are widely present.For Avermectins such as Ivermectin HCL and AVM hereinafter Rhzomorph, it may refer to such as " Ivermectin and Abamectin ", 1989, by M.H.Fischer and H.Mrozik, William C.Campbell, published by Springer Verlag. orEt al. (1981),"Avermectins Structure Determination",J.Am.Chem.Soc.,103,4216-4221.It is right In doramectin, it may refer to " Veterinary Parasitology ", vol.49, No.1, in July, 1993,5-15.For It is close than mycin class, can referring particularly to Davies H.G. et al., 1986, " Avermectins and Milbemycins ", Nat.Prod.Rep., 3,87-121, Mrozik H. et al., 1983, Synthesis of Milbemycins from Avermectins, Tetrahedron Lett., 24,5333-5336, U.S. Patent number 4,134,973 and EP 0 677 054.

Avermectins and Mi Bi mycins class show effective antiparasitic activities, while to most mammal kinds Class relative nontoxic.(/ close the focus for having turned into a large amount of chemical modifications research than mycin family, it can join as a result, AVM See such as U.S. patents 4,199,569；4,285,963；4,310,519；4,423,209；4,427,663；4,457,920,4, 806,527；4,831,016；4,855,317；4,859,657；4,871,719；4,873,224；4,874,749；4,895, 837；4,906,619,4,920,148；4,963,582；4,973,711；4,978,677；5,015,630,5,023,241,5, 030,622；5,055,454；5,055,596；5,057,499；5,077,308；5,162,363；5,169,839；5,208, 222；5,244,879；5,262,400；5,637,703；5,830,875；7,250,402；With EP 0 212 867；0 237 339；0 241 146；0 214 731；0 194 125；With 0 170 006, it is fully incorporated herein by quoting.Avermectin The further modification of plain family member is described in such as U.S. number of patent applications 10/488,225；10/498,858；10/513, 247；10/539,274；10/543,637；10/543,638；10/543,643,10/544,274；10/544,281；10/560, 390；10/568,715；10/599,671；11/317,932；11/319,686 and 11/319,687, by quoting its whole It is incorporated herein.Chemical modification induces also by with acid incorporation fermentation broth, is subsequently introduced the C-25 positions of Avermectins (EP 0 214 731 and Arch.Biochem.Biophys 1989,269,544-547).All these documents and its draw ginseng Document, and references cited herein are examined, all by quoting and being incorporated to.

Although anti-parasitic research has excellent progress, the report of increasing veterinary science parasitic animal and plant resistance is still Cause to worry (Parasitology 2005,131, S179-190).So as to still have always a demand for Combination nova in veterinary field Thing and therapy.It is an object of the invention to provide new preparaton, and it includes cyclic depsipeptide and macrolide, and uses the chemical combination The processing method of thing.As described herein, the present invention is astonishing, unexpected and non-obvious.

Although macrolide is well known anti-parasitic compound, still has always a demand for resisting the parasitic animal and plant constantly to develop and resist Property.Therefore, we have found that the combination of macrolide and cyclic depsipeptide, which effectively handles some resistant parasites, especially dog, dislikes silk Worm (Dirofilaria immitis), more particularly JYD-34 heart worms strain.

Cyclic depsipeptide especially cyclooctadepsipeptides such as PF1022A or Ai Modesi, it is by belonging to Secretin receptor family Stimulation presynaptic receptor act on myoneural junction, cause paralysis and the death of parasitic animal and plant.Cyclic depsipeptide of the present invention includes It is made up of and with the compound of 8 to 30 annular atoms, such as PF as ring structure unit amino acid and hydroxycarboxylic acid 1022A, Ai Modesi and US5380745, US 2003/0143254A1, US005571793A, US5514773 are described in, US5821222, US5646244, US5874530, US6159932, US5856436, US6033879, US5763221, US6329338, US6355615, US6265537, US6043058, US6146853, US6630569, US7285404, US7109018, US6916641, US6828300, US6900176, US7432102, US7763583, US2012302496, WO12/028556, US2015166608, US5777075, US6369028, US5116815, US5747448, US5116815 and US5380745 other compounds, are fully incorporated herein by quoting.

The present composition can also include secondary plum blossom-shaped mould acid amides (paraherquamide) compound and these changes The derivative of compound, including derquantel is (referring to Ostlind et al., Research in Veterinary Science,1990,48,260-61；With Ostlind et al., Medical and Veterinary Entomology, 1997,11,407-408).Secondary plum blossom-shaped mould amides compound is the activity with some parasitic animals and plants of confrontation of known class Compound, it include spiral shell dioxane heptadiene diindyl core (referring to Tet.Lett.1981,22,135； J.Antibiotics 1990,43,1380, and J Antibiotics 1991,44,492).It is in addition, relevant in structure Marcfortine class compounds, such as marcfortines A-C, and it is known and can be with preparaton phase group of the present invention Close (referring to J.Chem.Soc.-Chem.Comm.1980,601 and Tet.Lett.1981,22,1977).Secondary plum blossom-shaped mould acyl Other descriptions of amine derivative may refer to such as WO 91/09961, WO 92/22555, WO 97/03988, WO 01/ 076370, WO 09/004432 and US 2010/0197624, United States Patent (USP) 5,703,078 and United States Patent (USP) 5,750,695, lead to Cross to quote and be fully incorporated herein.The present composition can also include at least one extra general action described herein Property activating agent, including but not limited to one or more isoxazoline activating agents；Or the anthelmintic of other classifications, including one kind Or a variety of aminoacetonitriles activating agents, one or more aryl and pyrroles's -2- base cyano ethyl amino activating agents, or its combination.

It can also include soil actinomycete thorn saccharopolyspora strain (Saccharopolyspora in the present composition Spinosa multiple killing teichomycin caused by) (spinosyn) activating agent is (see, for example, Salgado V.L. and Sparks T.C., " The Spinosyns:Chemistry,Biochemistry,Mode of Action,and Resistance,"Comprehensive Molecular Insect Science, vol.6, pp.137-173,2005) or semi-synthetic class multiple killing teichomycin (spinosoid) activating agent.Multiple killing teichomycin class (spinosyns) be generally referred to as the factor or component A, B, C, D, E, F, G, H, J, K, L, M, N, O, P, Q, R, S, T, U, V, W or Y, and any number of in these components or its combination can be used for the present composition In.Multiple killing teichomycin compound can be fused to 12- membered macrolides 5,6,5- tri- ring ring systems, neutral sugar (rhamnose), and Amino sugar (forosamine).These and other natural multiple killing teichomycin compound, including can be used in the present composition 21- cyclobutenyls multiple killing teichomycin caused by Saccharopolyspora pagona, can be via routine techniques known in the art Ferment to produce.The other multiple killing teichomycin compounds that can be used in the present composition are disclosed in the U.S. patent No.s 5,496, 931；5,670,364；5,591,606；5,571,901；5,202,242；5,767,253；5,840,861；5,670,486；5, 631,155 and 6,001,981, all it is integrally incorporated herein by quoting.Multiple killing teichomycin compound can include but is not limited to more Killing teichomycin A, multiple killing teichomycin D, multiple killing teichomycin, ethyl pleocidin, or its combination.Multiple killing teichomycin is multiple killing teichomycin A and killed mould more Plain D combination, and ethyl pleocidin is 3 '-ethyoxyl -5,6- dihydro multiple killing teichomycin J and 3 '-ethyoxyl multiple killing teichomycin L group Close.

In some embodiments, composition can contain two or more multiple killing teichomycins (spinosyn) and/or class The combination of multiple killing teichomycin (spinosoid) activating agent.Such as in one embodiment, composition can include multiple killing teichomycin, It is multiple killing teichomycin A and multiple killing teichomycin D combination.It is also contemplated that other combinations.In yet another embodiment, composition can include Multiple killing teichomycin and/or class multiple killing teichomycin activating agent or its combination, and it is in combination described herein one or more extra General action activating agent, including but not limited to one or more isoxazoline activating agents, one or more macrolide activity Agent, one or more benzimidazole reagents include probenazole, oxibendazole, mebendazol, Fenbendazole, oxfendazole, rosickyite Carbendazim, Triclabendazole and febantel, or the anthelmintic of other classifications include levamisole, Pyrantel, Morantel, pyrrole Quinoline ketone, closantel, clorsulon, one or more aminoacetonitriles activating agents, one or more insect growth regulator, IGRs, Yi Zhonghuo A variety of anabasine activating agents or aryl and pyrroles's -2- base cyano ethyl amino activating agents, or its combination.

Phenylpyrazole is known in the art and are described in such as U.S. patent No.s 5,885,607 as a classification； U.S. the patent No. 6,010,710；U.S. the patent No. 6,083,519；U.S. the patent No. 6,096,329；U.S. the patent No. 6,395, 765, the U.S. patent No.s 6,867,229, EP-A-295,217, EP-A-352,944 and the U.S. patent No.s 5,576,429；U.S. The number of patent application 11/825,050 of the patent No. 5,122,530, U.S. and EP 295 177, by the disclosure of which and the ginseng of reference Document is examined to be incorporated herein by quoting.The known excellent activity having to insect such as tick and flea of the insecticides, and at certain One of these compounds 1- [2,6-Cl in a little embodiments₂-4-CF₃Phenyl] -3-CN-4- [SO-CF₃]-5-NH₂Pyrazoles or fluorine Worm nitrile can be included among the compositions and methods of the invention.

The present invention combination of at least one cyclic depsipeptide and at least one macrolide comprising effective dose, in processing to extremely A kind of few anthelmintic macrolide shows unexpected synergistic effect when showing the parasitic animal and plant of resistance.

At least one cyclic depsipeptide and at least one macrolide comprising effective dose the present invention combination, processing to according to Dimension rhzomorph shows unexpected synergistic effect when showing the parasitic animal and plant of resistance.

At least one cyclic depsipeptide such as Mo Desi and at least one macrolide such as Ivermectin HCL comprising effective dose The present invention combination, prevention resistance heart worm strain three instar larvaes (L3) and four instar larvaes (L4) avoid its into It is ripe to show unexpected synergistic effect when being adult.

Synergistic effect has been described as " the cooperation effect of two kinds of components (such as component (a) and component (b)) in the mixture, Its total effect is higher than or is longer than the adduction of two kinds of (or a variety of) component independents " (referring to P.M.L.Tames, Neth.J Plant Pathology 1964,70,73-80).At least one cyclic depsipeptide and at least one macrolide containing effective dose Mixture be found displaying to the synergistic effects of some important pest and disease damages.At least one cyclic depsipeptide of effective dose and at least one The successful combination of kind macrolide provides relative monotherapy and (is confined to a kind of medicine of medicine such as macrolide or cyclic depsipeptide Thing processing) improve and even synergy effect, especially for parasitic animal and plant resistant strain such as heart worm resistant strain.

If macrolide and cyclic depsipeptide exist in the present invention combines with some weight ratios, synergistic effect is then special Significantly.However, the weight ratio of macrolide and cyclic depsipeptide in combination can change in relatively wide scope.Generally, Present invention combination includes the macrolide and cyclic depsipeptide of given preferred ratio.

The condition that adduction or synergistic effect can be obtained is to work as macrolide and cyclic depsipeptide：(1) co-formulation and in group Give or deliver simultaneously in the unit dosage form preparaton of conjunction；(2) as separated preparaton alternating or parallel delivering；Or (3) make With some other schemes.In the case where alternating treatment delivers, the condition that can obtain adduction or synergistic effect is macrolide Give or deliver successively with cyclic depsipeptide, such as be separately administered orally in different unit dosage forms.Generally, in the alternating treatment phase Between, each active component of effective dose successively give by (order)；And in conjoint therapy, two or more work of effective dose Property composition is given together.

The present composition can also be in including but not limited to oral preparaton, injectable preparaton, and it is local, pour, The various forms of skin or subcutaneous preparaton.Preparaton it is expected to give to mammal.The example of mammal includes but unlimited In people, dog, cat and other livestocks or domestic mammals.The present composition can in suitable in the form of oral use, such as As bait formulation (see, for example, U.S. Patent number 4,564,631, be fully incorporated herein by quoting), dietary supplements, contain Ingot, lozenge, masticatory, tablet, hard or soft capsule, pill (bolus), emulsion are aqueous or molten containing oil suspension, the aqueous solution or oil Liquid, oral filling agent, dispersible pulvis or granule, pre-composition, syrup or elixir, casing preparaton or paste.It is expected to use Any means known to being used to preparing pharmaceutical composition according to this area in the composition of oral use are prepared and institute State composition and can contain and be selected from sweetener, bitters, flavouring, one or more reagents of colouring agent and preservative are to provide Pharmaceutical elegant and nice preparation.

Tablet can contain active component, and it is mixed with the nontoxic pharmaceutically acceptable excipient for being suitable to prepare tablet Close.These excipient can be such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate for example, inert diluent；It is granulated And disintegrant, for example, cornstarch, or alginic acid；Binding reagents, such as starch, gelatin or Arabic gum, and lubricant, for example, Magnesium stearate, stearic acid or talcum, the tablet can be uncoated or they can be coated with by known technology and prolonged Slow disintegration and absorption in the gastrointestinal tract are simultaneously accordingly provided in the continuous action in longer time section.It is, for example, possible to use delay Material such as glyceryl monostearate or glycerol distearate.They can also by being described in the U.S. patent No.s 4,256, 108；4,166,452；Be coated with forming use with the technology of 4,265,874 (being all fully incorporated herein by quoting) In the osmotic therapeutic tablets of controlled release.

The preparaton of oral use can be hard gelatin capsule, wherein active component and inert solid diluent such as carbonic acid Calcium, calcium phosphate or white bole mixing.Capsule can also be Perle, active component and water or can wherein be mixed with water molten Agent such as propane diols, various PEG and ethanol, or oil medium such as peanut oil, liquid paraffin or olive oil mixing.

The present composition can also be oil-in-water or water-in-oil emulsion form.Oil phase can be vegetable oil, for example, olive Oil or peanut oil, or mineral oil, for example, liquid paraffin or these mixture.Suitable emulsifying agent can be natural phospholipid, For example, soybean lecithin, and ester or partial ester derived from aliphatic acid and hexitol anhydrides, such as Sorbitan list oleic acid Ester, and the condensation product of the partial ester and oxirane, such as polyoxyethylene sorbitan monoleate.The emulsion is also Sweetener, bitters, flavouring, and/or preservative can be contained.

In a kind of embodiment of preparaton, the present composition can be microemulsion form.Microemulsion is fitted well In as liquid-carrier medium.Microemulsion is the quaternary system for including aqueous phase, oil phase, surfactant and cosurfactant System.They are translucent and isotropic liquid.

Microemulsion forms as follows：The stable dispersions of droplet of the aqueous phase in oil phase, or on the contrary oil phase in aqueous phase The stable dispersions of droplet.The size of these droplets is less than 200nm (and being 1000 to 100000nm to emulsion).Interfacial film is by table Face activity (SA) and altogether surface-active (Co-SA) molecule alternating composition, it is by reducing the spontaneous shape of interfacial tension microemulsion Into.

In a kind of embodiment of oil phase, oil phase can be formed from mineral or vegetable oil, formed from unsaturated polysaccharide-based Change glyceride or formed from triglycerides, or alternatively form the mixture from the compound.In a kind of embodiment party of oil phase In formula, oil phase can include triglycerides；In the another embodiment of oil phase, triglycerides is medium chain triglyceride, such as C₈-C₁₀Caprylic/capric triglyceride.In yet another embodiment, the %v/v scopes that oil phase can account for are selected from about 2 to about 15%； About 7 to about 10%；About 8 to about 9%v/v microemulsions.

Aqueous phase can include such as water or ethylene glycol derivative, such as propane diols, glycol ether, polyethylene glycol or glycerine. In a kind of embodiment of ethylene glycol derivative, ethylene glycol can be selected from propane diols, diethylene glycol monoethyl ether, dipropylene glycol list second Ether and its mixture.Usually, the ratio accounted for is about 1 to about 4%v/v in microemulsion by aqueous phase.

Surfactant for microemulsion can include diethylene glycol monoethyl ether, dipropylene glycol monomethyl ether, Pegylation C₈-C₁₀Glyceride or the dioleate of polyglycereol -6.In addition to these surfactants, cosurfactant can also include Short chain alcohol, such as ethanol and propyl alcohol.

In a kind of embodiment of the amount of surfactants/cosurfactants, cosurfactant and surface-active The ratio of agent is about 1/7 to about 1/2.In the another embodiment of the amount of cosurfactant, in microemulsion exist about 25 to About 75%v/v surfactant and about 10 to about 55%v/v cosurfactant.

Can so it be prepared containing oil suspension：Active component is suspended in vegetable oil, such as peanut oil, olive oil, sesame In oil or coconut oil, or in mineral oil such as liquid paraffin.It can contain thickener containing oil suspension, for example, beeswax, firmly Paraffin or cetanol.Sweetener such as sucrose can be added, saccharin or aspartame, bitters, and flavouring are nice to provide Oral formulations.These compositions can be able to preservation by adding antioxidant such as vitamin C or other known preservative.

Aqueous suspension can contain active material, and it is mixed with the excipient suitable for preparing aqueous suspension.The tax Shape agent is suspending agent, for example, carmethose, methylcellulose, hydroxyl-propyl methylcellulose, mosanom, polyvinyl Pyrrolidones, bassora gum and Arabic gum；Scattered or wetting agent can be natural phospholipid, such as lecithin, or alkylene oxide With the condensation product of aliphatic acid, such as Myrj 45, or oxirane and the condensation product of long chain aliphatic, example Such as, 17 ethyleneoxy group cetanol, or oxirane and the condensation product derived from aliphatic acid and the partial ester of hexitol, such as Octadecanoic acid ester of polyethylene glycol, or oxirane produce with the condensation derived from aliphatic acid and the partial ester of hexitol anhydrides Thing, such as polyoxyethylene sorbitol monoleate.Aqueous suspension can also contain one or more preservatives, such as P-hydroxy Benzoic Acid ester ethyl ester, or p-hydroxy Benzoic Acid ester n-propyl, one or more colouring agents, one or more flavorings Agent, and one or more sweeteners and/or bitters, such as those described above.

Suitable for water prepares the dispersible pulvis of aqueous suspension and granule can be provided and disperseed or wetting agent by adding, Suspending agent and the active component of one or more preservatives mixing.Suitable scattered or wetting agent and suspending agent are such as above Those referred to.Can also there are extra excipient, such as sweetener, bitters, flavouring and colouring agent.

Syrup and elixir can be prepared with Sweetening agents such as glycerine, propane diols, sorbierite or sucrose.The preparation Agent can also contain moderator, preservative, flavouring and/or colouring agent.

In another embodiment of the invention, the composition can be paste form.Paste form embodiment Example includes but is not limited in U.S. Patent number 6,787,342 and 7,001,889 (being incorporated herein it each via quoting) retouch Those stated.In addition to the compounds of this invention, paste can also further contain Fumed silica；Viscosity is adjusted Agent；Carrier；Optionally, absorbent；Optionally, colouring agent, stabilizer, surfactant or preservative.

In a kind of embodiment of preparaton, the preparaton can be paste, and it contains the compounds of this invention, steam Deposit silica, viscosity modifier, absorbent, colouring agent；And hydrophilic support, it is glyceryl triacetate, and monoglyceryl ester is sweet Oily diester or triglycerides.

Paste can also include, but not limited to viscosity modifier, selected from PEG 200, PEG 300, PEG 400, PEG 600, monoethanolamine, triethanolamine, glycerine, propane diols, polyoxyethylene (20) sorbitan monooleate (polyoxyethylene sorbitan monoleate Or Tween 80), and poloxamer (for example, Pluronic L 81)；Absorbent, selected from magnesium carbonate, calcium carbonate, starch, and fiber Element and its derivative；And colouring agent, selected from titanium dioxide, iron oxide, and FD＆C indigo plant #1 aluminum lakes.

Composition can be the aqueous or oily suspensions form of sterile injectable.The suspension can be according to known technology Prepared with the suitable scattered or wetting agent of those already mentioned above and suspending agent.The preparation of sterile injectable can also be in nothing The solution or suspension through the sterile injectable in parenteral-acceptable diluent or solvent of poison, e.g. 1,3- fourths two Solution in alcohol.Water is especially referred in workable acceptable medium and solvent, Ringer's solution and isotonic sodium chloride are molten Liquid.Cosolvent such as ethanol, propane diols, glycerol formal or polyethylene glycol can also be used.Preservative can be used, than Such as phenol or phenmethylol.

In addition, sterile, fixed oil can routinely be used as solvent or suspension media.For the intention, it can use and appoint Anticipate gentle fixed oil, include one-or diglyceride of synthesis.In addition, aliphatic acid such as oleic acid can be used for preparing injectable agent.

Local, skin and subcutaneous preparaton can include as non-limiting examples, emulsion, creme, ointment, gel, Paste, powder, shampoo, sprinkle and pour preparaton, i.e., with preparaton, smear agent solution and suspension, drops and spray.Of the present invention group The local application of compound includes liniment, spray or sprinkles and pours agent composition, and it can cause the present composition to pass through skin Absorb to realize systemic level, the level of whole hair is distributed or realized on a skin surface by sebaceous glands.In chemical combination In the case that thing is by sebaceous glands distribution, they can serve as bank, and can now have longer lasting effects (up to count Month).Smear preparaton and be typically applied in regional area, it refers to the region of not whole mammal.The one of regional area In kind of embodiment, the part can be between shoulder.In yet another embodiment, regional area can be band, such as from Mammal head to afterbody band.

Sprinkle and pour preparaton and be described in U.S. Patent number 6,010,710, it is incorporated herein also by quoting.Sprinkle pour preparaton can be with Advantageously oiliness, and generally comprise the diluent or medium of active component, if active component can not in diluent It is molten, then also include solvent (such as organic solvent).

The organic solvent that can be used in the present invention includes but is not limited to：Citroflex A-4, fatty acid ester is such as Fatty acid ester dimethyl ester, diisobutyl adipate, acetone, acetonitrile, phenmethylol, butyldiglycol, dimethyl acetamide, dimethyl Formamide, dipropylene glycol n-butyl ether, ethanol, isopropanol, methanol, ethylene glycol monoethyl ether, glycol monoethyl ether, monomethyl acetyl Amine, dipropylene glycol monomethyl ether, liquid polyoxyethylene glycol, propane diols, 2-Pyrrolidone (such as 1-METHYLPYRROLIDONE), two is sweet At least two mixture in alcohol list ether, ethylene glycol and diethyl phthalate, or these solvents.

As medium or diluent, it can be mentioned that vegetable oil is for example, but soybean oil is not limited to, peanut oil, castor oil, jade Rice bran oil, levant cotton oil, olive oil, grape-kernel oil, sunflower oil, coconut oil etc.；Mineral oil for example, but is not limited to, vaseline, stone Wax, organosilicon, etc.；Aliphatic series or cyclic hydrocarbon or alternatively for example middle chain (such as C8 to C12) triglycerides.

In another embodiment of the invention, softening agent can be added and/or sprawled and/or film forming agent.A kind of real Apply in mode, softening agent and/or spreading agent and/or film forming agent can be：

(a) copolymer of PVP, polyvinyl alcohol, vinyl acetate and vinyl pyrrolidone, poly- second Glycol, phenmethylol, mannitol, glycerine, sorbierite, the sorbitan alcohol ester of polyoxyethylene；Lecithin, carboxylic first fiber Plain sodium, silicone oil, polydiorganosiloxanepolyurea oil (such as dimethyl silicone polymer (PDMS) oil), such as that containing silanol-functional A bit, or 45V2 is oily,

(b) anion surfactant such as alkali stearates, odium stearate, potassium stearate or ammonium stearate；It is stearic Sour calcium, triethanolamine stearate salt；Sodium abietate；Salt (such as the sodium salt of lauryl sulfate and the sulfuric acid whale of alkyl sodium sulfate ester The sodium salt of cerul ester)；Neopelex, dioctyl sodium sulphosuccinate；Aliphatic acid (such as that derived from coconut oil A bit),

(c) the formula N of cationic surfactant such as water soluble⁺R'R"R"'R"",Y^-Quaternary ammonium salt, wherein residue R are optional Hydroxylated hydrocarbon residue and Y^-It is anion ratio such as halide, sulfuric acid and the sulfonic acid anion of strong acid；Cetyl trimethyl bromine Change ammonium and belong to the cationic surfactant that can be used,

(d) formula N⁺HR'R " R' " amine salt, wherein residue R are optional hydroxylated hydrocarbon residues；Octadecyl amine hydrochloride category In the cationic surfactant that can be used,

(e) nonionic surfactant such as sorbitan alcohol ester, its be optionally polyoxyethylene (such as Polyoxyethylene sorbitan monoleate), the alkyl ether of polyoxyethylene；The fatty alcohol of polyoxy propylated such as polyoxypropylene-styrene ether； Polyethylene glycol stearate, the derivative of the polyoxyethylene of castor oil, polyglycerol ester, the fat of polyoxyethylene The copolymer of alcohol, the aliphatic acid of polyoxyethylene, oxirane and expoxy propane,

(f) the substituted bay based compound of amphoteric surfactant such as glycine betaine；Or

(g) in these reagents at least two mixture.

Solvent and the concentration of the compounds of this invention and their solubility in the solvent proportionally use.Reality should be made great efforts Now volume as small as possible.Difference is complemented to 100% with medium.

In a kind of embodiment of the amount of softening agent, softening agent ratio used can be about 0.1 to 50% or 0.25 to 5% volume.In yet another embodiment, softening agent ratio used can be about 0.1% to about 30%, about 1% to about 30%, about 1% to about 20%, or about 5% to about 20% volume.

In another embodiment of the invention, composition can be ready to use solution form, and it is described in U.S. Patent number 6,395,765, it is incorporated herein by quoting.In addition to the compounds of this invention, ready to use solution can also contain crystallization inhibitor, Organic solvent and organic cosolvent.

In a kind of embodiment of the amount of crystallization inhibitor, crystallization inhibitor can with about 1 to about 30% (w/v) or about The ratio of 5 to about 15% is present.In other embodiments, amount of the crystallization inhibitor in preparaton of the present invention can be about 1% to about 20%, about 1% to about 15%, or about 1% to about 10% (w/w).

In some embodiments, organic solvent can have about 10 to 35 or about 20 to 30 dielectric constants, and this has Content of the solvent in total composition represents the magnitude of recruitment for reaching 100% composition.

In some embodiments, organic cosolvent can have the boiling point under about 100 DEG C or under about 80 DEG C. In other embodiments, organic cosolvent can have under about 250 DEG C, under about 230 DEG C, under about 210 DEG C Or the boiling point under about 200 DEG C.In other embodiments, organic cosolvent can have about 10 to 40 or about 20 to 30 Dielectric constant.In some embodiments, cosolvent can be in the composition with about 1/15 to 1/2 organic cosolvent/have Solvent w/w (W/W) ratio is present.Solvent, which can improve solubility or serve as to dry, starts agent, and can be mixed with water And/or mixed with organic solvent.

Preparaton can also include the antioxidant for it is expected to suppress air oxidation, and the presence ratio of the reagent is selected from by about The scope that 0.005 to about 1% (w/v) and about 0.01 to about 0.05% is formed.

The type of crystallization inhibitor used is unrestricted in preparaton of the present invention, as long as its effective inhibitory activity agent or nothing Activating agent is crystallized or precipitated from preparaton.Crystallization inhibitor available for the present invention can include but is not limited to：

(a) copolymer of PVP, polyvinyl alcohol, vinyl acetate and vinyl pyrrolidone, poly- second The polyoxyethylene of glycol, phenmethylol, 1-METHYLPYRROLIDONE, mannitol, glycerine, sorbierite or Sorbitan Ester；Lecithin or carmethose；Or acrylic acid derivative, such as methacrylic etc.；

(b) anion surfactant, such as alkali stearates (such as odium stearate, potassium or ammonium)；Calcium stearate or Triethanolamine stearate salt；Sodium abietate；The salt of alkyl sodium sulfate ester, it includes but is not limited to the sodium salt of lauryl sulfate and sulphur The sodium salt of sour spermaceti base ester；Neopelex or dioctyl sodium sulphosuccinate；Or aliphatic acid (such as coconut oil)；

(c) cationic surfactant, such as the formula N of water soluble⁺R'R " R' " R " " Y- quaternary ammonium salts, wherein R residues are phases With or different optional hydroxylated hydrocarbon residues and Y- be strong acid anion, such as halide, sulfuric acid and sulfonic acid anion；Ten Six alkyl trimethyl ammonium bromides are one of cationic surfactants that can be used；

(d) formula N⁺HR'R " R' " amine salt, wherein R residues are identical or different optional hydroxylated hydrocarbon residues；Octadecane Base amine hydrochlorate is one of cationic surfactant that can be used；

(e) nonionic surfactant, such as the ester of the optional polyoxyethylene of Sorbitan, such as poly- mountain Pear ester 80, or the alkyl ether of polyoxyethylene；Polyethylene glycol stearate, the derivative of the polyoxyethylene of castor oil Thing, polyglycerol ester, the fatty alcohol of polyoxyethylene, the aliphatic acid or oxirane and expoxy propane of polyoxyethylene Copolymer；

(f) amphoteric surfactant, such as the substituted bay based compound of glycine betaine；Or (g) above-mentioned (a)-(f) institutes At least two mixture in the compound of row.

In a kind of embodiment of crystallization inhibitor, it will be matched using crystallization inhibitor.Above-mentioned pairing includes, such as high The combination of molecule type film forming agent and surfactant.These reagents are using selected from the chemical combination referred to above as crystallization inhibitor Thing.

In a kind of embodiment of film forming agent, the reagent is polymer type, and it includes but is not limited to various grades PVP, polyvinyl alcohol, and the copolymer of vinyl acetate and vinyl pyrrolidone.

In a kind of embodiment of surfactant, the reagent includes but is not limited to by nonionic surfactant structure Into those；In the another embodiment of surfactant, the reagent is the polyoxyethylene of Sorbitan Ester, and in the another embodiment of surfactant, the reagent includes the polysorbate of various grades, such as poly- sorb Ester 80.

In another embodiment of the invention, crystallization inhibitor that film forming agent and surfactant can refer to elsewhere Added in the range of the limitation of total amount with similar or identical amount.

Thus the pairing formed ensures such target in a manner of noticeable：Crystallization is not present on fur and protects Hold the cosmetic appearance of skin or animal skin；Namely also no adhesion tendency or sticky outward appearance are inclined under the high concentration of active material To.

In a kind of embodiment of antioxidant, the reagent it is conventional in the art those and include but is not limited to Butylated Hydroxyanisole, Butylated Hydroxytoluene, vitamin C, sodium pyrosulfite, propyl gallate, sodium thiosulfate or they in be no more than two kinds Mixture.

Formulation aid discussed above is known to practitioner in the art and is commercially available or by known skill Art obtains.These concentrate compositions are typically prepared by the way that component as defined hereinabove is simply mixed；Advantageously, starting point is Active material is mixed into primary solvent, then adds other compositions or auxiliary agent.

The volume applied can be about 0.3 to about 1ml magnitude.In a kind of embodiment of volume, the volume It can be about 0.5ml magnitudes to cat, and can be about 0.3 to dog to about 3ml magnitudes, depending on mammal weight.

In another embodiment of the invention, in the case where solution is applied into mammal or birds, using root Lasting for a long time and wide spectrum effect can also be provided according to the smearing preparaton of the present invention.Smearing preparaton offer will concentrate molten Liquid, suspension, microemulsion or emulsion are dosed topically for the site that interval is applied on mammal, typically between two shoulders (liniment type solution).

For smearing preparaton, carrier can be described in U.S. Patent number 6,426,333 (being incorporated herein by quoting) Liquid-carrier medium, smear preparaton a kind of embodiment in its can include solvent and cosolvent, wherein described Solvent is selected from acetone, acetonitrile, phenmethylol, butyldiglycol, dimethyl acetamide, dimethylformamide, dipropylene glycol normal-butyl Ether, ethanol, isopropanol, methanol, ethylene glycol monoethyl ether, glycol monoethyl ether, mono methyl acetamide, dipropylene glycol monomethyl ether, liquid Body polyoxyethylene glycol, propane diols, 2-Pyrrolidone (such as 1-METHYLPYRROLIDONE), diethylene glycol monoethyl ether, ethylene glycol, adjacent benzene At least two in dicarboxylate fatty acid ester, such as diethylene adipate or diisobutyl adipate, and these solvents Mixture and the cosolvent selected from absolute ethanol, isopropanol or methanol.

Liquid-carrier medium can optionally contain crystallization inhibitor, and it is selected from anion surfactant, cation Surfactant, nonionic surfactant, amine salt, amphoteric surfactant or PVP, polyvinyl alcohol, second The copolymer of vinyl acetate and vinyl pyrrolidone, polyethylene glycol, phenmethylol, mannitol, glycerine, sorbierite, polyoxy are sub- Ethylating sorbitan alcohol ester；Lecithin, carmethose, and acrylic acid derivative, or these crystallization inhibitors Mixture.

Smearing preparaton can be by being dissolved in active component pharmaceutically or prepared by veterinary science acceptable medium.Separately Selection of land, smearing preparaton can be by the way that active component packing be prepared so as to which the residue of therapeutic agent is retained in into mammal Surface.Depending on the species of host mammal to be treated, the seriousness and type and host's body weight of infection, these preparations Agent will change with the therapeutic agent weight in combination.

Each formulation can contain about 0.5mg to about 5g each activating agent.It is described in a kind of embodiment of formulation Dosage is about 1mg to about 500mg activating agents, typically about 25mg, about 50mg, about 100mg, about 200mg, about 300mg, about 400mg, about 500mg, about 600mg, about 800mg, or about 1000mg.

In one embodiment of the invention, each activating agent can be in the formulation with about 0.05 to about 10% weight The concentration of amount/volume is present.In another embodiment of the invention, activating agent can be in the formulation with about 0.1 to 2% weight The concentration of amount/volume is present.In another embodiment of the invention, activating agent can be in the formulation with about 0.25 to about The concentration of 1.5% weight/volume is present.In another embodiment of the invention, activating agent can be in the formulation with about 1% The concentration of weight/volume is present.

In one embodiment of the invention, be administered activating agent can with any various intervals (such as it is daily, weekly or Monthly) carry out, and dosage, frequency and pattern that each reagent is administered can individually determine.For example, administration cyclic depsipeptide and Macrolide can be per hour, daily, weekly, monthly, the event that annual or single is carried out.In a preferred embodiment, give Medicine cyclic depsipeptide and macrolide are monthly carried out.In addition, administration can have the duration of 6 months to 1 year or longer.

It should be understood that in another embodiment of the invention, the activating agent in combination can be in identical or different medicine Give or give successively simultaneously in thing preparaton.In another embodiment of the invention, active compound can be via perfusion Give, and can part or orally administration.It is those to irrigate preparaton, is fed wherein the liquid containing the present composition is given The mouth or throat of newborn animal, or it is poured onto the skin or fur of mammal.

The present invention also relates to the present composition that ectoparasite effective dose is killed by giving to handle mammal confrontation The method of ectoparasite infestation.The mammal that can be handled includes but is not limited to people, cat and dog.

In an embodiment for treatment confrontation ectoparasite, the ectoparasite is one or more insect or spider shapes Animal, include following category those, Ctenocephalus (Ctenocephalides), Rh (Rhipicephalus), remove from office tick Belong to (Dermacentor), Isodesspp (Ixodes), Boophilus (Boophilus), Ambylomma, Haemaphysalis (Haemaphysalis), Hyalomma (Hyalomma), Sarcoptesspp (Sarcoptes), Psoroptesspp (Psoroptes), Notoedres (Otodectes), Psoroptes (Chorioptes), Hypoderma (Hypoderma), Damalinia (Damalinia), Linognathus (Linognathus), Haematopinus (Haematopinus), Solenoptes, Trichodectes (Trichodectes), and Felicola (Felicola)。

In the another embodiment for the treatment of confrontation ectoparasite, the ectoparasite comes from following category：Ctenocephalus (Ctenocephalides), Rh (Rhipicephalus), Dermacentor (Dermacentor), Isodesspp (Ixodes) And/or Boophilus (Boophilus).The ectoparasite for the treatment of includes but is not limited to flea, tick, mite, mosquito, fly, lice, calliphorid and its group Close.Specific example includes but is not limited to cat and dog flea (ctenocephalides felis (Ctenocephalides felis), Ctenocephalus (Ctenocephalides sp.) etc.), tick (Rh (Rhipicephalus sp.), Isodesspp (Ixodes sp.), leather Tick category (Dermacentor sp.), Amblyoma sp. etc.), and mite (Demodex (Demodex sp.), Sarcoptesspp (Sarcoptes sp.), Notoedres (Otodectes sp.) etc.), lice (Trichodectes (Trichodectes sp.), Cheyletiella (Cheyletiella sp.), Lignonathus sp., etc.), mosquito (Aedes (Aedes sp.), Culex (Culex Sp.), Anopheles (Anopheles sp.), etc.) and fly (Hematobia sp., Musca (Musca sp.), Genus Stomoxys (Stomoxys sp.), Dematobia sp., Callitroga (Cochliomyia sp.), etc.).In treatment confrontation ectoparasite In another embodiment, the ectoparasite is flea and/or tick.

The additional examples of ectoparasite include but is not limited to Boophilus (Boophilus), particularly boophilus microplus, colour killing ox Those of tick and Boophilus annulatus kind；Fly-blown such as human botfly (Dermatobia hominis) (Brazil be referred to as Berne) and Cochliomyia hominivorax (lucilia)；Sheep fly-blown such as lucilia sericata (Lucilia sericata), lucilia cuprina (Lucilia cuprina) (in Australia, New Zealand and South Africa are referred to as green dermatomyiasis linearis migrans).Dipteron fly, that is, adult is parasitic Those of thing, such as west horn fly (Haematobia irritans)；Lice such as sheep jaw lice (Linognathus Vitulorum) etc.；With mite such as Sarcoptes scabici and sheep scabies mite (Psoroptes ovis).Above-mentioned list is not It is exhaustive and it is well known that other ectoparasites are harmful to animals and humans.These include, such as the Diptera larvae of migration.

It can also be used for handling confrontation endoparasite in the present composition, such as selected from those following worms：Naked head Tapeworm category (Anaplocephala), Ancylostoma (Ancylostoma), Anecator, Ascaris (Ascaris), capillary line Eimeria (Capillaria), Cooperia (Cooperia), Diplopylidium (Dipylidium), Dirofilaria (Dirofilaria), Echinococcus (Echinococcus), Enterobius (Enterobius), fluke category (Fasciola), blood lance line Worm (Haemonchus), Oesophagostumum, ostertagi category (Ostertagia), Belascaris (Toxocara), class Strongylus (Strongyloides), Toxascaris (Toxascaris), Trichinella (Trichinella), Trichocephalus , and Trichostrongylus (Trichostrongylus) (Trichuris).

In another embodiment of the invention, compound of the invention and composition are suitable to preventing and treating pest and disease damage and are such as selected from Following insects：Groton bug (Blatella germanica), tobacco budworm (Heliothis virescens), potato Chrysomelid (Leptinotarsa decemlineata), Pavement Ant (Tetramorium caespitum) and combinations thereof.

Plant parasitic nematodes include, such as goitre Turbatrix (Anguina spp.), Aphelenchoides (Aphelenchoides spp.), Belonoaimus spp., Bursaphelenchus (Bursaphelenchus spp.), rise Suede grass blade nematode (Ditylenchus dipsaci), ball Heterodera (Globodera spp.), Heliocotylenchus Spp., Heterodera (Heterodera spp.), minute hand Turbatrix (Longidorus spp.), Meloidogyne (Meloidogyne spp.), Pratylenchus (Pratylenchus spp.), Radopholus similis Throne (Radopholus Similis), spiral Turbatrix (Rotylenchus spp.), burr Turbatrix (Trichodorus spp.), Tylenchorhynchus (Tylenchorhynchus spp.), pulvinulus sword Turbatrix (Tylenchulus spp.), Tylenchulus Semipenetrans (Tylenchulus Semipenetrans), Xiphinema (Xiphinema spp.).

In addition, no matter with or without the other agricultural chemicals reagents for adding composition, the present invention can also be used for treating other diseases Insect pest, it includes but is not limited to following pest and disease damages：

(1) Isopoda (Isopoda), such as damp worm (Oniscus asellus), Armadillidium vulgare and Pillworm (Porcellio scaber)；

(2) Diplopoda (Diplopoda), such as Blaniulus guttulatus；

(3) lip foot mesh (Chilopoda), such as Geophilus carpophagus and common house centipede category (Scutigera spp.)；

(4) Symphyla (Symphyla), such as kahikatea worm (Scutigerella immaculata)；

(5) Thysanoptera (Thysanura), such as silverfiss (Lepisma saccharina)；

(6) Collembola (Collembola), such as arms Onychiurus arcticus (Onychiurus armatus)；

(7) Blattaria (Blattaria), such as oriental cockroach (Blatta orientalis), American cockroach (Periplaneta americana), leucophaea maderae (Leucophaea maderae) and Groton bug (Blattella germanica)；

(8) Hymenoptera (Hymenoptera), such as Diprion (Diprion spp.), real tenthredinidae (Hoplocampa Spp.), hair ant category (Lasius spp.), MonomoriumMayr (Monomorium pharaonis) and Vespa (Vespa spp.)；

(9) Siphonaptera (Siphonaptera), such as Xanthopsyllacheopis (Xenopsylla cheopis) and Ceratophyllus (Ceratophyllus spp.)；

(10) Anoplura (Anoplura) (Phthiraptera), for example, Damalinia (Damalinia spp.), Haematopinus (Haematopinus spp.), Linognathus (Linognathus spp.), Pediculus (Pediculus spp.), Trichodectes (Trichodectes spp.)；

(11) Arachnoidea (Arachnida), for example, Acarus siro (Acarus siro), citrus aceria (Aceria Sheldoni), peronium Eriophyes (Aculops spp.), acupuncture Eriophyes (Aculus spp.), Amblyomma (Amblyomma Spp.), Argas (Argas spp.), Boophilus (Boophilus spp.), short whisker Acarapis (Brevipalpus spp.), Bryobia praetiosa (Bryobia praetiosa), Psoroptes (Chorioptes spp.), Dermanyssus gallinae (Dermanyssus Gallinae), Eotetranychus (Eotetranychus spp.), goitre mite (Epitrimerus pyri) on pears, true Tetranychus (Eutetranychus spp.), Eriophyes (Eriophyes spp.), half Tarsonemus (Hemitarsonemus spp.), Hyalomma (Hyalomma spp.), Isodesspp (Ixodes spp.), erythema spider (Latrodectus mactans), Metatetranychus spp., Oligonychus (Oligonychus spp.), Ornithodoros (Ornithodoros spp.), Instep line is eaten in Panonychus citri category (Panonychus spp.), citrus wrinkle leaf Aculus (Phyllocoptruta oleivora), side more Mite (Polyphagotarsonemus latus), Psoroptesspp (Psoroptes spp.), Rh (Rhipicephalus Spp.), Rhizoglyphus (Rhizoglyphus spp.), Sarcoptesspp (Sarcoptes spp.), Middle East gold scorpion (Scorpio Maurus), Stenotarsonemus spp., Tarsonemus (Tarsonemus spp.), Tetranychus (Tetranychus Spp.), tomato tiltedly carries on the back aceria (Vasates lycopersici)；

(12) Bivalva, for example, decorations shellfish category (Dreissena spp.)；

(13) coleoptera (Coleoptera), for example, acanthoscelides obtectus (Acanthoscelides obtectus), beak rutelian Belong to (Adoretus spp.), blue hair stern firefly is chrysomelid (Agelastica alni), click beetle category (Agriotes spp.), potato Gill cockchafer (Amphimallon solstitialis), furniture death watch beetle (Anobium punctatum), Genus Anoplophora Hope (Anoplophora spp.), flower is as belonging to (Anthonomus spp.), Anthrenus (Anthrenus spp.), Ah gill cockchafer Belong to (Apogonia spp.), hidden food first category (Atomaria spp.), the moth-eaten category (Attagenus spp.) of fur, Bruchidius Obtectus, bean weevil category (Bruchus spp.), ceutorhynchus (Ceuthorhynchus spp.), Bei Wei Aralia curculionids (Cleonus Mendicus), wide chest click beetle category (Conoderus spp.), root neck is as belonging to (Cosmopolites spp.), brown New Zealand's rib wing The melolonthid (Costelytra zealandica), Curculio (Curculio spp.), the hidden beaks of Yang Gan as (Cryptorhynchus lapathi), khapra beetle category (Dermestes spp.), chrysomelid category (Diabrotica spp.), food are planted Ladybug category (Epilachna spp.), Faustinus cubae, globose spider beetle (Gibbium psylloides), black different pawl sugarcane gold Tortoise (Heteronychus arator), Hylamorpha elegans, North America house longhorn beetle (Hylotrupes bajulus) are purple Cloverleaf is as (Hypera postica), brown bark beetle category (Hypothenemus spp.), sugarcane hock gill cockchafer brown greatly (Lachnosterna consanguinea), colorado potato beetles (Leptinotarsa decemlineata), Lissorhoptrusoryzophilus (Lissorhoptrus oryzophilus), cylinder beak is as belonging to (Lixus spp.), the moth-eaten category (Lyctus spp.) of powder, cauliflower dew tail First category (Meligethes) aeneus, gill cockchafer in May (Melolontha melolontha), Migdolus spp., black longicorn Belong to (Monochamus spp.), Naupactus xanthographus, golden spider beetle (Niptus hololeucus), coconut palm moth rhinoceros Cockchafer (Oryctes rhinoceros), saw-toothed grain beetle (Oryzaephilus surinamensis), black grape ear image (Otiorrhynchus sulcatus), small blue and white cockchafer (Oxycetonia jucunda), the chrysomelid (Phaedon of horseradish ape Cochleariae), food phyllobranchia cockchafer category (Phyllophaga spp.), Japan popillia flavosellata fairmaire (Popillia japonica), Premnotrypes spp., flea phyllotreta (Psylliodes) chrysocephala, Ptinus (Ptinus spp.) are dark-coloured Ladybug (Rhizobius ventralis), lesser grain borer (Rhizopertha dominica), Sitophilus (Sitophilus spp.), Sharp Rhynchophorus (Sphenophorus spp.), stem is as belonging to (Sternechus spp.), comprehensive mesh (Symphyletes Spp.), Cabot's Tragopan (Tenebrio molitor), Tribolium (Tribolium spp.), spot khapra beetle category (Trogoderma Spp.), seed is as belonging to (Tychius spp.), Xylotrechus Chevrolat (Xylotrechus spp.), away from ground beetle category (Zabrus spp.)；

(14) Diptera (Diptera), such as Aedes (Aedes spp.), Anopheles (Anopheles spp.), flower Garden march fly (Bibio hortulanus), Calliphora (Calliphora erythrocephala), Mediterranean fruitfly (Ceratitis capitata), Carysomyia (Chrysomyia spp.), Callitroga (Cochliomyia spp.), bite people's knurl Fly (Cordylobia anthropophaga), Culex (Culex spp.), Cuterebra (Cuterebra spp.), olive Fruit fly (Dacus oleae), human botfly (Dermatobia hominis), Drosophila (Drosophila spp.), Fannia (Fannia spp.), Gasterophilus (Gastrophilus spp.), Hylemyia (Hylemyia spp.), Hippobosca (Hyppobosca spp.), Hypoderma (Hypoderma spp.), Liriomyza (Liriomyza spp.), Lucilia (Lucilia spp.), Musca (Musca spp.), Bemisia spp (Nezara spp.), Oestrus (Oestrus spp.) are auspicious Allusion quotation frit fly (Oscinella frit), spinach spring fly (Pegomyia hyoscyami), Phorbia (Phorbia spp.), Genus Stomoxys (Stomoxys spp.), Gadfly (Tabanus spp.), Tannia spp., European daddy-longlegs (Tipula Paludosa), Wohlfahrtia (Wohlfahrtia spp.)；

(15) Gastropoda (Gastropoda), such as A Yong Limaxs (Arion spp.), Biomphalaria (Biomphalaria spp.), Bulinus (Bulinus spp.), grey Limax (Deroceras spp.), native snail category (Galba spp.), Lymnaea (Lymnaea spp.), Katayama (Oncomelania spp.), amber spiro spp (Succinea spp.)；

(16) worm, such as Ancylostoma duodenale (Ancylostoma duodenale), Ancylostoma Ceylanicum, Acylostoma braziliensis, Ancylostoma (Ancylostoma spp.), Ascaris (Ascaris) lubricoides, Ascaris (Ascaris spp.), cloth Shandong, Malaysia nematode (Brugia malayi), Brugia Timori, Bunostomum (Bunostomum spp.), Xia Baite Turbatrixs (Chabertia spp.), Clon (Clonorchis spp.), Cooperia (Cooperia spp.), Dicrocoelium (Dicrocoelium spp) are thread Net filaria (Dictyocaulus filaria), bothriocephalus cordatus (Diphyllobothrium latum), Dracunculus medinensis, Echinococcus granulosus (Echinococcus granulosus), Echinococcus Multilocularis, pinworm (Enterobius vermicularis), Faciola spp., haemonchus (Haemonchus Spp.), Heterakis (Heterakis spp.), Hymenolepis nana (Hymenolepis nana), Hyostrongulus Spp., Loa (Loa) Loa (Loa), Nematodirus (Nematodirus spp.), oesophagostomum (Oesophagostomum spp.), Opisthorchis (Opisthorchis spp.), filaria volvulus (Onchocerca Volvulus), ostertagi category (Ostertagia spp.), Paragonimus (Paragonimus spp.), Schistosomen spp., Strongyloides fuelleborni, strongyloides intestinalis (Strongyloides Stercoralis), Stronyloides spp., taeniarhynchus saginatus (Taenia saginata), taeniasis suis (Taenia Solium), trichina(Trichinella spiralis) (Trichinella spiralis), Trichinella nativa, Trichinella Britovi, Trichinella nelsoni, Trichinella pseudopsiralis, Trichostrongulus spp., Whipworm (Trichuris trichuria), wuchereria bancrofti (Wuchereria bancrofti)；

(17) Semiptera (Heteroptera), such as squash bug (Anasa tristis), Antestiopsis Spp., native chinch bug category (Blissus spp.), pretty fleahopper category (Calocoris spp.), Campylomma livida, different back of the body length Stinkbug category (Cavelerius spp.), Cimex (Cimex spp.), Creontiades dilutus, Dasynus piperis, Dichelops furcatus, pepper lace bug (Diconocoris hewetti), red cotton bug category (Dysdercus spp.) are beautiful Continent stinkbug category (Euschistus spp.), Eurygasterspp category (Eurygaster spp.), Heliopeltis spp., Horcias Nobilellus, Leptocorisa spp category (Leptocorisa spp.), Leptoglossus phyllopus, Lygus Hahn (Lygus Spp.), Macropes excavatus, Miridae (Miridae), Bemisia spp (Nezara spp.), Oebalus spp., Pentomidae, square butt stinkbug (Piesma quadrata), wall stinkbug category (Piezodorus spp.), cotton fleahopper (Psallus Seriatus), Pseudacysta persea, Rhodnius (Rhodnius spp.), Sahlbergella singularis (Sahlbergella Singularis), Scotinophora spp., pear crown network pentatomidae (Stephanitis nashi), Tibraca spp., vertebra hunts stinkbug Belong to (Triatoma spp.)；

(18) Homoptera (Homoptera), for example, Acyrthosipon spp., Aeneolamia spp., Agonoscena spp., Aleyrodes (Aleurodes spp.), sugarcane split aleyrodid (Aleurolobus barodensis), aleyrodid Category (Aleurothrixus spp.) , Mango leafhopper category (Amrasca spp.), welted thistle short-tail aphid (Anuraphis cardui), Kidney Aspidiotus category (Aonidiella spp.), the short aphid of pears (Aphanostigma piri), Aphis (Aphis spp.), grape leaf Cicada (Arboridia apicalis), roundlet armored scale category (Aspidiella spp.), Aspidiotus category (Aspidiotus spp.), Atanus spp., Aulacorthumsolani (Aulacorthum solani), Aleyrodes (Bemisia spp.), Lee short-tail aphid (Brachycaudus helichrysii), Brachycolus spp., brevicoryne brassicae (Brevicoryne brassicae) are small Brown back rice plant hopper (Calligypona marginata), Carneocephala fulgida, cane powder angle aphid (Ceratovacuna Lanigera), Cercopidae (Cercopidae), lecanium category (Ceroplastes spp.), knurl nail hair aphid in strawberry (Chaetosiphon fragaefolii), Chionaspis tegalensis, tea green leafhopper (Chlorita onukii), core Peach blackspot aphid (Chromaphis juglandicola), brown Aspidiotus category (Chrysomphalus ficus), corn leafhopper (Cicadulina mbila), Coccomytilus halli, soft a red-spotted lizard category (Coccus spp.), the hidden knurl aphid of tea Fischer (Cryptomyzus ribis), Dalbulus spp., Aleyrodes (Dialeurodes spp.), tangerine Psylla spp (Diaphorina spp.), it is white to carry on the back armored scale category (Diaspis spp.), Doralis spp., carry out giant coccid category (Drosicha Spp.), western rounded tail Aphis (Dysaphis spp.), grey mealybug category (Dysmicoccus spp.), green jassids category (Empoasca spp.), woolly aphid category (Eriosoma spp.), Erythroneura spp category (Erythroneura spp.), Euscelis Bilobatus, coffee ground mealybug (Geococcus coffeae), phony disease of peach poison leafhopper (Homalodisca coagulata), Mealy plum aphid (Hyalopterus arundinis), icerya purchasi category (Icerya spp.), piece angle leafhopper category (Idiocerus Spp.), flat beak leafhopper category (Idioscopus spp.), small brown rice planthopper (Laodelphax striatellus), ball a red-spotted lizard category (Lecanium spp.), lepidosaphes shimer (Lepidosaphes spp.), radish aphid (Lipaphis erysimi), long tube Aphis (Macrosiphum spp.), Mahanarva fimbriolata, sorghum aphid forest type (Melanaphis sacchari), Metcalfiella spp., wheat is without net aphid (Metopolophium dirhodum), the black flat wing spot aphid (Monellia of edge Costalis), Monelliopsis pecanis, tumor aphid genus (Myzus spp.), lettuce patch up Macrosiphus spp (Nasonovia Ribisnigri), rice green leafhopper category (Nephotettix spp.), brown paddy plant hopper (Nilaparvata lugens), Oncometopia spp., Orthezia praelonga, red bayberry edge aleyrodid (Parabemisia myricae), potato wood louse Belong to (Paratrioza spp.), Parlatoria (Parlatoria spp.), Pemphigus (Pemphigus spp.), popcorn Wing plant hopper (Peregrinus maidis), Phenacoccus (Phenacoccus spp.), Yang Ping wing woolly aphids (Phloeomyzus Passerinii), phorodon aphid (Phorodon humuli), Japan's Aphis (Phylloxera spp.), lily and armored scale (Pinnaspis aspidistrae), stern line mealybug category (Planococcus spp.), pyriform original giant coccid (Protopulvinaria pyriformis), white mulberry scale (Pseudaulacaspis pentagona), mealybug category (Pseudococcus spp.), Psylla spp (Psylla spp.), tiny golden wasp category (Pteromalus spp.), Pyrilla Spp., large bamboo hat with a conical crown and broad brim Aspidiotus category (Quadraspidiotus spp.), Quesada gigas, thorn mealybug category (Rastrococcus is put down Spp.), Rhopalosiphum (Rhopalosiphum spp.), black bourch category (Saissetia spp.), Scaphoides Titanus, green bugs (Schizaphis graminum), sago cycas thorn Aspidiotus (Selenaspidus articulatus), Long clypeus plant hopper category (Sogata spp.), white backed planthopper (Sogatella furcifera), planthopper category (Sogatodes Spp.), three horned frogs (Stictocephala festina), Tenalaphara malayensis, U.S.'s walnut black aphid (Tinocallis caryaefoliae), wide chest froghopper category (Tomaspis spp.), sound Aphis (Toxoptera spp.), temperature Room aleyrodid (Trialeurodes vaporariorum), individual Psylla spp (Trioza spp.), jassids category (Typhlocyba Spp.), sharp armored scale category (Unaspis spp.), grape phylloxera (Viteus vitifolii.)；

(19) Isoptera (Isoptera), for example, Reticulitermes (Reticulitermes spp.), odontotermes (Odontotermes spp.)；

(20) Lepidoptera (Lepidoptera), for example, Sang Jian Autographa spps (Acronicta major), are tired of noctuid (Aedia Leucomelas), ground Noctua (Agrotis spp.), Alabama argillacea, evil spirit's Noctua (Anticarsia is done Spp.), lopper worm (Barathra brassicae), Bucculatrix thurberiella, loose powder butterfly geometrid moth (Bupalus piniarius), yellow tail leaf roller (Cacoecia podana), Capua reticulana, codling moth (Carpocapsa pomonella), orchard autumn geometrid moth (Cheimatobia brumata), straw borer spp (Chilo spp.), Dragon spruce Choristoneura spp (Choristoneura fumiferana), grape codling moth (Clysia ambiguella) (Clysia ambiguella), Noctuid (Earias insulana), Anagasta kuehniella (Ephestia bore in Cnaphalocerus spp., Egypt Kuehniella), pornography and drug moth (Euproctis chrysorrhoea), cuts Noctua (Euxoa spp.), Feltia spp., Galleria mellonella waxmoth (Galleria mellonella), Helicoverpa spp., Heliothis (Heliothis spp.) are brown to knit moth (Hofmannophila pseudospretella), Homonamagnanima (Homona magnanima), apple ermine moth (Hyponomeuta padella), Beet armyworm category (Laphygma spp.), thin moth category (Lithocolletis) Blancardella, green fruit winter noctuid (Lithophane antennata), Loxagrotis albicosta, Euproctis (Lymantria spp.), malacosoma neustria (Malacosoma neustria), lopper worm (Mamestra Brassicae), Mocis repanda, Mythimna separata, Oria spp., Oulema oryzae (Oulema Oryzae), small noctuid (Panolis flammea), pink bollworm (Pectinophora gossypiella), citrus leaf is dived Moth (Phyllocnistis citrella), Pier (Pieris spp.), diamondback moth (Plutella xylostella), tiltedly Autographa spp category (Prodenia spp.), puppet grind Noctua (Pseudaletia spp.), soybean chi noctuid (Pseudoplusia Includens), corn borer (Pyrausta nubilalis), Beet armyworm category (Spodoptera spp.), Thermesia Gemmatalis, bag rain moth (Tinea pellionella), Tineolabisselliella (Tineola bisselliella), the green volume moth of oak (Tortrix viridana), Trichoplusiaspp (Trichoplusia spp.)；

(21) Orthoptera (Orthoptera), such as residential house Chinese mugwort Xi (Acheta domesticus), oriental cockroach (Blatta orientalis), Groton bug (Blattella germanica), Gryllotalpa spp (Gryllotalpa spp.), horse Moral draws blattaria (Leucophaea maderae), migratory locusts category (Locusta spp.), black locust category (Melanoplus spp.), U.S. The big Lian in continent (Periplaneta americana), desert locust (Schistocerca gregaria)；

(22) Thysanoptera (Thysanoptera), such as rice thripses (Baliothrips biformis), Enneothrips Flavens, flower thrips category (Frankliniella spp.), Heliothis (Heliothrips spp.), greenhouse Hercinothrips spp (Hercinothrips femoralis), card Thrips (Kakothrips spp.), grape thrips (Rhipiphorothrips Cruentatus), hard Thrips (Scirtothrips spp.), Taeniothrips (Taeniothrips) cardamoni, thrips Belong to (Thrips spp.)；

(23) protozoan, such as eimeria (Eimeria spp.).

In each side of the present invention, compound of the invention and composition can be directed to independent pest and disease damage or its combination progress Using.

Extra medicine, agricultural chemicals or veterinary science active component can also be included but is not limited to, parasiticide includes killing Mite agent, anthelmintic, interior ectoparasite agent (endectocide) and insecticide are killed, add the present composition.Anti-parasitic Agent can include killing ectoparasite agent and kill endoparasitism agent.Veterinary science medicament is well known in the art (see, for example, Plumb ' Veterinary Drug Handbook,5^th Edition,ed.Donald C.Plumb,Blackwell Publishing, Or The Merck Veterinary Manual, (2005) 9^thEdition, (January 2005)) and including but it is unlimited In acarbose, acepromazine maleate, paracetamol, acetazolamide, sodium acetazolamide, acetic acid, acetohydroxamic acid, second Acyl cysteine, Acitretin, ACV, A Fu Ranas, albendazole, ALBUTEROL SULFATE, alfentanil HCl be not fast Alcohol, alprazolam, Altrenogest, amantadine HCl, amikacin sulfate, aminocaproic acid, centrine hydrosulphuric acid salt, ammonia Theophylline/theophylline, amiodarone HCl, Amitraz, amitriptyline HCl, Amlodipine Besylate Tablet, ammonium chloride, ammonium molybdate, Amoxicillin, Amoxicillin, potassium clavulanate, amphotericin B dexycholate, the amphotericin B based on lipid, ampicillin, Amprolium HCl, antiacid (oral), antivenin, apomorphine HCl, apramycin sulfate, vitamin C, asparaginase, Ah Take charge of a woods, atenolol, Atipamezole HCl, Atracurium Besilate, atropine sulfate, Anranofin (aurnofin), Jin Liu Portugals Sugar, azaperone, imuran, azithromycin, Baclofen, barbiturate, benazepil HCl, betamethasone, chlorine shellfish courage Alkali, Bisacody, basic bismuth salicylate, bleomycin sulfate, boldenone undecylenate, bromide, bromocriptine methanesulfonate, Budenoside, buprenorphin hydrochloride, buspirone hydrochloride, busulfan, butorphanol tartrate, Cabergoline, salmon drop calcium Element, calcitriol, calcium salt, captopril, carindacillin sodium, Carbimazole, carboplatin, Carnitine, Carprofen, Carvedilol, head Spore amoxycillin, Cefazolin sodium, Cefixime, cefoperazone sodium, Cefotaxime Sodium, Cefotetan Disodium, cefoxitin sodium, head Spore moors oxime ester, cefotaxime, ceftiofur sodium, Ceftiofur HCl, ceftriaxone sodium, cefalexin, cynnematin, cephalo Woods, charcoal (activation), Chlorambucil, chloramphenicol, chlorine nitrogenChlorine nitrogen+/- clidinium bromide, chlorothiazide, chlorphenamine maleate Quick, chlorpromazine hydrochloride, chlorpropamide, aureomycin, chorionic gonadotrophin (HCG), chromium, Cimetidine, Ciprofloxacin, Cisapride is suitable Platinum, citrate, CLA, mecloprodin fumarate, clenbuterol HCl, clindamycin, Clofazimine, hydrochloric acid chlorine rice Pa is bright, Clonazepam, clonidine, Cloprostenol Sodium, chlorine nitrogenDipotassium, clorsulon, Cloxacillin, codeine phosphate, autumn waters -- limid eyes Celestial alkali, corticotropin (ACTH), cosyntropin, endoxan, ring born of the same parents element, cyproheptadine HCl, cytarabine, Dacarbazine, put Line rhzomorph D/ actinomycin Ds, Dalteparin Sodium, DANAZOL, dantrolene sodium, dapsone, Decoquinate, deferoxamine mesylate salt, ground Drawing is examined former times, Deslorelin acetate, minirin acetate, desoxycortone pivalate, Detomidine HCl, ground plug rice Pine, Dexpanthenol, dexrazoxane, dextran, diazepam, diazoxiide (oral), diclofenamide, DDVP, C14H10Cl2NNaO2, Dicloxacillin, hetrazan, diethylstilbestrol (DES), Difloxacin HCl, digoxin, dihydrotachysterol (DHT), ground that sulphurHCl, dramamine, dimercaprol/BAL, dimethyl sulfoxide, dinoprost tromethamine, hydramine HCl, the third pyrrole Amine phosphate, dobutamine hydrochloride, more storehouse ester/DSS, dolasetron mesilate, domperidone, Dopamine hydrochloride, more clarkes Fourth, doxapram hydrochloride, doxepin hydrochloride, doxorubicin hydrochloride, Doxycycline, edetate calcium disodium, ethylenediamine tetra-acetic acid Calcium, Edrophonium Chloride, enalapril/enalaprilat, Enoxaparin Sodium, Enrofloxacin, ephedrine sulfate, adrenaline, according to pool Spit of fland/erythropoietin(EPO), Eprinomectin, epsiprantel, erythromycin, esmolol hydrochloride, cycloprovera, Yi Tani Acid/ethacrynate sodium, ethanol (ethanol), etidronate, Etodolac, Etomidate, be euthanized agent w/ amobarbitals, and method is not For fourth, aliphatic acid (required/omega), Felbamate, Fenbendazole, fentanyl, ferrous sulfate, Filgrastim, Finasteride, Ethiprole, Florfenicol, Fluconazole, Flucytosine, fludrocortison acetate, Flumazenil, flumethasone, Flunixin Portugal first Amine, fluorouracil (5-FU), Prozac, the third vinegar fluticasone, fluvoxamine maleate, Fomepizole (4-MP), furazolidone, Frusemide, Gabapentin, gemcitabine HCl, sulmycin, Glimepiride, Glipizide, glucagons, sugared cortex Steroids reagent, Glucosamine/chondroitin sulfate, glutamine, glibenclamide, glycerine (oral), glycopyrronium bromide, dagger-axe that Rayleigh, griseofulvin, gualfenesin, fluothane, hemoglobin glutamer -200Heparin, HES, Sodium Hyaluronate, hydralazine HCl, Hydrochioro, hydrocodone bitartrate, hydrocortisone, Hydromorphone, hydroxycarbamide, Hydroxyzine, ifosfamide, imidacloprid, imidocarb dipropionate, imipenem-Cilastatin Sodium, imipramine, Amrinone lactic acid Salt, insulin, interferon alfa-2a (human recombinant), iodide (sodium/potassium), ipecac (syrup), sodium lopodate, dextran Iron, isoflurane, isoprel HCl, isotretinoin, Isoxsuprine HCl, Itraconazole, Ivermectin HCL, white bole/pectin, Ketamine HCl, ketoconazole, Ketoprofen, ketorolac tromethamine, lactulose, leuproside, levamisole, Levetiracetam, left first Shape parathyrine sodium, lidocaine HCl, lincomycin HCl, Cyronine, lisinopril, lomustine (CCNU), lufenuron, rely Propylhomoserin, magnesium, mannitol, Marbofloxacin, mustargen HCl, meclozine HCl, Meclofenamic Acid, Medetomidine HCl, medium chain triglyceride three Ester, medroxyprogesterone acetate, megestrol acetate acetate, Melarsomine, melatonin, Meloxicam, melphalan, meperidine HCl, mercapto are fast Purine, Meropenem, melbine HCl, methadone HCl, methazolamide, methenamine mandelate/hippurate, first mercapto miaow Azoles, methionine, methocarbamol, methohexital sodium, methotrexate (MTX), methoxyflurane, methylenum careuleum, methylphenidate, methylprednisolone, methoxy Emetisan HCl, metoprolol, metronidaxole, mexiletine HCl, Mibolerone, midazolam HCl is close to compare mycin (milbemycin) oxime, mineral oil, minocycline HCl, Misoprostol, mitotane, mitoxantrone HCl, Morantel wine Stone hydrochlorate, morphine sulfate, Moxidectin, naloxone HCl, abolon, naproxen, the analgesia of arcotic (opium) activator Medicine, bykomycin, neostigmine, niacinamide, Nitazoxanide, Nitenpyram, furantoin, nitroglycerin, sodium nitroprussiate sodium, Nizatidine, novobiocin monosodium, nystatin, Octreotide acetate, olsalazine sodium, Omeprazole, Ondansetron, opium stop Cathartic, Orbifloxacin, oxacillin sodium, Oxazepam, oxfendazole, Oxybutynin Chloride, Oxymorphone HCl, oxygen Fourth Ring Element, oxytocin, Pamidronate Disodium, pancreplipase, Pancuronium Bromide, paromomycin sulfate, parozetine HCl, Penicillamine, general information penicillins, penicillin, ospeneff, pentazocine, yellow Jackets, Pentosan Polysulfate Sodium, hexanone can Theobromine, pergolide mesilate, phenobarbital, phenoxybenzamine HCl, phenylbutazone, neo-synephrine HCl, Super Odrinex HCl, dilantin sodium, pheromones class, parenteral phosphoric acid, vitamin K1/phytomenadione, Pimobendan, piperazine, Pirlimycin HCl, piroxicam, the glycosaminoglycan of polysulfide acidifying, ponazuril, potassium chloride, pralidoxime chloride, praziquantel, prazosin HCl, sprinkle Ni Songlong/metacortandracin, Primidone, procainamide HCl, procarbazine HCl, prochlorperazine, propantheline bromide, sore blister propionic acid bar Bacterium (Propionibacterium acnes) injection, Propofol, Propranolol HCl, protamine sulfate, pseudoephedrine HCl, Metamucil, pyrantel pamoate, Pyridostigmine Bromide, pyrilamine maleate, pyrimethamine, mepacrine HCl, quinindium, ranitidine HCl, rifampin, s- adenyl residues-methionine (SAMe), salt solution/hyperosmolar agent, take charge of clarke Fourth (selamectin), selegiline HCL/l- obtain deprenyl, Sertraline HCl, sevelemer HCl, sevoflurane, and silymarin/ Milk thistle, sodium acid carbonate, sodium polystyrene sulfonate, stibii natrii gluconas, sodium sulphate, sodium thiosulfate, somatotropin, rope he Luo Er HCl, spectinomycin HCl, spirolactone, Stanozolol, streptokinase, streptozotocin, Succimer, choline succinate dichloride dihydrate, Ulcerlmin, sufentanil citrate, Prinzone (Squibb), sulphadiazine/trimethroprim, Sulfamethoxazole/methoxy benzyl Pyridine, sulfadimethoxine (sulfadimentoxine), sulfadimethoxine/Ormetoprim, SASP, taurine are husky for pool Woods, terbinafline HCl, terbutaline sulfate, testosterone, tetracycline HCl, probenazole, Thiacetarsamide Sodium, vitamin B1HCl, thioguanine, pentothal, thiotepa, thyroid-stimulating hormone, Tiamulin, ticarcillin disodium, Tiletamine HCl/ Zolazepam HCl, tilmocsin, Tiopronin, tobramycin sulfate, tocainide HCl, tolazoline HCl, Tolfenamic Acid, Topiramate, C16H25NO2 HCl, Triamcinolone acetonide, trientine HCl, Trilostane, alimemazine tartrate w/ prednisolones, bent pyrrole That quick HCl, Tylosin, urdosiol, valproic acid, vanadium, vancomycin HCl, pitressin, Vecuronium Bromide, Verapamil HCl are long Spring alkali sulfate, leucocristine sulfate, vitamin E/selenium, Warfarin sodium, Xylazine HCl, yogimbine HCl, zafirlukast, together More husbands are fixed (AZT), zinc acetate/zinc sulfate, Zonisamide and its mixture.

In one embodiment of the invention, aryl pyrazole compound can be added the present composition.Aryl pyrrole Azoles includes but is not limited to be described in the U.S. patent No.s 6,001,384；6,010,710；6,083,519；6,096,329；6,174, 540；6,685,954 and 6,998,131 those (be all incorporated herein by quoting, each authorize Merial, Ltd., Duluth,GA)。

, can be (a kind of by knot robe sour (nodulisporic acid) and its derivative in another embodiment of the invention Known acaricide, pest repellant, anti-phage agent and insecticide) add the present composition.These compounds are used for treating or in advance Infection in anti-human and animal and such as U.S. patent No.s 5,399,582,5,962,499,6,221,894 and 6 are described in, 399,786, it is fully incorporated herein by quoting.Composition can include knot robe acid (nodulisporic known in the art Acid the those in) one or more in derivative, including whole stereoisomers, such as literature cited described above.

In another embodiment of the invention, the referred to as acaricide or insecticide class of insect growth regulator, IGR (IGRs) The present composition can also not added.The compound for belonging to such is known to practitioner and covers not assimilating for wide scope Learn classification.These compounds are all worked by the development or growth of interference insect pest and disease damage.Insect growth regulator, IGR describes In such as U.S. Patent number 3,748,356；U.S. Patent number 3,818,047；U.S. Patent number 4,225,598；U.S. Patent number 4,798,837；U.S. Patent number 4,751,225, EP 0 179 022 or U.K.2 140 010 and U.S. Patent number 6,096, 329 and 6,685,954 (authorizing Merial Ltd., Duluth, GA), are fully incorporated herein by quoting.It is adapted in use to IGRs example can include but is not limited to methoprene, Nylar, hydroprene, cyromazine, fluazuron, lufenuron, fluorine acyl Urea, pyrethroid, carbonamidine and 1- (2,6- difluoro benzoyl) -3- (2- fluoro- 4- (trifluoromethyl) phenylureas.

Pest repellant that can be combined with the present composition can be benzene disulfonic acid amide compound, and it includes but is not limited to clorsulon；Or teniacide, it includes but is not limited to praziquantel, Pyrantel or morantel.

Parasiticide that can be combined with the present composition can be biologically active peptide or protein matter bag Include but be not limited to depsipeptides, it belongs to the presynaptic receptor of secretin receptor family by stimulating and works and draw in myoneural junction Play paralysis and the death of parasitic animal and plant.In one embodiment, depsipeptides can be Ai Modesi.

Insecticide that can be combined with the present composition can be that multiple killing teichomycin (spinosyn) (kills mould more such as Element) or substitution pyridyl methyl derivatives compound such as imidacloprid.Such reagent describes as above, and for example, is described in U.S. the patent No. 4,742,060 or EP 0 892 060, are fully incorporated herein by quoting.The technical merit of practitioner will It is enough to determine which kind of single compound can be used for preparaton of the present invention to treat special insect infection.For endoparasite, The parasiticide that can be combined includes but is not limited to Pyrantel, morantel, benzimidazole (including albendazole, thiophene Benzene imidazate, probenazole, TBZ, febantel, sulphur oxygen benzene azoles, the third oxygen benzene azoles, triclabendazole, mebendazole and how Toby Amine), levamisole, closantel, Lei Fusha how (rafoxanide), nitroxinil, Dimphenol and secondary plum blossom-shaped mould Acid amides (paraherquamide).For ectoparasite, the insecticide that can be combined also includes but is not limited to pyrethroid, Organophosphorus compounds and anabasine such as imidacloprid, and compound such as metaflumizone, Amitraz and Ryanicide (ryanodine) receptor antagonist.

When suitable, pest repellant, parasiticide and insecticide, which are also selected from being described above, is suitable to agriculture chemistry purposes Compounds.

Generally, extra agricultural chemicals reagent can be included with about 0.1 μ g to about 10mg dosage.A kind of in the present invention implements In mode, extra agricultural chemicals reagent can be included with about 1 μ g to about 10mg dosage.In another embodiment of the invention, Extra agricultural chemicals reagent can be included with the dosage of about 5 to about 200 μ g/kg weight of mammal.In the another implementation of the present invention In mode, extra agricultural chemicals reagent can be included with about 0.1 to about 10mg/kg weight of mammal dosage.The present invention's In another embodiment, extra agricultural chemicals reagent can be included with about 0.5 to 50mg/kg dosage.

Another embodiment of the invention includes being used for the diagnostic tool for testing parasitic animal and plant strain presence or absence.For example, US20070042354, US20110223599,20030129680,20110223599 is open for identifying that it is parasitic that subject infects System, the method and composition of thing.

Although the present invention is by described in its embodiment, it should be understood that it can further be modified；And this Any change, purposes or the modification for covering the present invention it is expected in application, and it generally follows the principle of the present invention；And in institute of the present invention The deviation included within the known or conventional practice in field from the disclosure is related to, it goes for the required feature being described above With following scope of the following claims.The present invention with applicable law allowed be at utmost included in this paper various aspects or Whole modifications of theme described in claim and equivalent.

The some aspects of the present invention are further described by following embodiments：

Embodiment

Following embodiments are provided to illustrate some embodiments of the present invention, but are not construed in any way to this hair The limitation of bright scope.

Research Ivermectin HCL and the Ai Modesi points of effects opened and combine to heart worm (Dirofilaria immitis) Power：

Research be：10 males and 10 female sex-health beagles, 5.2 to 6.2 monthly ages, body weight 7.3 to 10.3kg.

Into before studying, test the microfilaria of dog and heart worm antigen and receive overall physical inspection.The 7th My god, it is inoculated with 50 infectiousness three ages heart worm larvas (JYD-34 separation strains) for each dog.In the 111st day blood to collection Antigen test is carried out, confirms that animal is not exposed to heart worm before inductive infection.

Based on the 2nd day body weight successively decreased in sex, 4 district's groups of each 5 dogs of composition.In district's groups, by drawing lots dog One of be randomly assigned to 5 treatment groups, and using the moon as interval orally processing 5 times, the processing is using the moon as dosage dosing interval With Ivermectin HCL oral administration solution, the combination of Profender tablets or Ivermectin HCL solution and Profender tablets is carried out, such as Shown in table 1 below：

Table 1：

All animals are human at the 160th day to be euthanized and is autopsied to reclaim parasitic animal and plant, counts the work of single dog Heart worm number.The percentage effect for the treatment of group is listed in table 1.

In this study, Ivermectin HCL solution (6mcg/kg) and Profender tablets (5mg/kg Ai Modesi+25mg/ Kg praziquantels) combine and orally give 5 months, there is provided to 100% effect of the inductive infection of heart worm JYD-34 separation strains.

Although the preferred embodiment of the present invention described above, it should be understood that the present invention that above-mentioned paragraph defines is not The detail being confined in description above, reason are that its many significant change is the possible master without departing from the present invention Purport or scope.

Claims (28)

1. treating or preventing the method for parsitism in mammal, including effective dose is given to the mammal：

A) at least one cyclic depsipeptide；With

B) at least one macrolide；

And pharmaceutically acceptable carrier；

Wherein parsitism is included to resistant parasitic animal and plant is individually handled or prevented with macrolide.

2. method according to claim 1, also comprising praziquantel or epsiprantel or its combination.

3. method according to claim 1, wherein effective dose are adduction effective dose or enhancing effective amount.

4. method according to claim 1, wherein parasitic animal and plant are heart worm (Dirofilaria immitis).

5. method according to claim 1, wherein parasitic animal and plant are resistance heart worm strains.

6. method according to claim 1, wherein parasitic animal and plant are three instar larvaes (L3) or four ages of resistance heart worm strain Phase larva (L4) or its combination.

7. method according to claim 1, wherein cyclic depsipeptide are 24- member cyclooctadepsipeptides.

8. method according to claim 1, wherein cyclic depsipeptide are Ai Modesi (emodepside), PF1022A, PF1022A Derivative or its combination.

9. method according to claim 1, wherein cyclic depsipeptide are Ai Modesi.

10. method according to claim 1, wherein the macrolide given is AVM (avermectin), it is close to compare mycin (milbemycin) or it is combined.

11. method according to claim 1, wherein the macrolide given is selected from AVM, Dimasdectin, more clarkes Rhzomorph (latidectin), thunder cuticulin are replaced in fourth, emamectin benzoate, Eprinomectin, Ivermectin HCL, drawing (lepimectin), selamectin (selamectin), it is close than mycin oxime and Moxidectin (moxidectin) or its combination；And

Cyclic depsipeptide is selected from Ai Modesi, PF1022A, and PF1022A derivative or its combination.

12. method according to claim 1, wherein the macrolide given is selected from AVM, Dimasdectin, more clarkes Rhzomorph replace in fourth, emamectin benzoate, Eprinomectin, Ivermectin HCL, drawing, thunder cuticulin, selamectin, it is close than mycin oxime with Moxidectin or its combination.

13. the macrolide of method according to claim 1, wherein composition is Ivermectin HCL.

14. the weight ratio of method according to claim 1, wherein macrolide and cyclic depsipeptide is 1:100 to about 1:1000, or About 1:500 to about 1:1000.

15. method according to claim 1, wherein veterinary composition are oral preparatons, injectable preparaton, local to prepare Agent, sprinkle and pour agent preparaton, skin preparaton or subcutaneous preparaton.

16. method according to claim 1, wherein veterinary composition are oral preparatons.

17. method according to claim 1, wherein parsitism are endoparasite infection.

18. method according to claim 1, wherein parasitic animal and plant are shown at least one resistance selected from following macrolides： Rhzomorph, thunder skin are replaced in AVM, Dimasdectin, doramectin, emamectin benzoate, Eprinomectin, Ivermectin HCL, drawing Rhzomorph, selamectin are close than mycin-oxime, and Moxidectin or its combination.

19. method according to claim 1, wherein parasitic animal and plant show the resistance to Ivermectin HCL.

20. method according to claim 1, wherein mammal are selected from the mankind, dog and cat.

21. method according to claim 1, wherein mammal are dog or cat.

22. method according to claim 1, wherein the treatment or prevention to parsitism in mammal are gone out except heart worm Three instar larvaes (L3) or four instar larvaes (L4) of (Dirofilaria immitis) so that it is adult that they are immature.

23. method according to claim 1, wherein parsitism cause the mammal respiratory system relevant with heart worm Disease.

24. giving for method according to claim 1, wherein cyclic depsipeptide and macrolide is to accompany to carry out.

25. giving for method according to claim 1, wherein cyclic depsipeptide and macrolide is carried out successively.

26. the method for administration of method according to claim 1, wherein cyclic depsipeptide and macrolide is identical.

27. method according to claim 1, wherein cyclic depsipeptide and macrolide are that interval is carried out 5 times to the moon is given.

28. method according to claim 1, including give effective dose to the mammal：

A) cyclic depsipeptide, it is Ai Modesi or PF1022A；With

B) macrolide is selected from AVM, Dimasdectin, doramectin, emamectin benzoate, Eprinomectin, according to dimension Rhzomorph is replaced in rhzomorph, drawing, thunder cuticulin, and selamectin is close than mycin oxime and Moxidectin；

And pharmaceutically acceptable carrier；

Wherein parsitism is included to resistant parasitic animal and plant is individually handled or prevented with macrolide.